. _:b418708961 . . . . _:b418708960 . _:b418708679 . . _:b418708963 . . _:b418708962 . _:b6412215 . . _:b418708973 . _:b418708738 . _:b418709132 . . _:b418708972 . . _:b418708975 . . . _:b418708974 . . _:b418708590 . _:b418708969 . _:b418708996 . _:b418708581 . _:b418709351 . _:b418708574 . . _:b418708772 . . _:b418708968 . _:b418709302 . . _:b418708958 . _:b418708971 . . _:b418709221 . . . _:b418708970 . _:b6412234 . . _:b418709007 . _:b418708981 . _:b418708889 . _:b418708980 . . . _:b418708579 . _:b418708983 . . _:b418708562 . . . . _:b418708982 . . . . _:b418708533 . _:b418708977 . . _:b418708976 . _:b418709211 . . _:b418709102 . _:b418708979 . . . _:b418708978 . . _:b418708989 . . . _:b418708988 . . . . _:b6412265 . _:b418708991 . _:b418708670 . _:b418708990 . _:b6412223 "Consistent with a role of TNF in contributing to dopaminergic neuron death in chronic parkinsonism, plasma TNF levels were shown to remain elevated in MPTP-treated non-human primates one year after administration of the neurotoxin [>>88<<]. In contrast, studies involving mice deficient in TNF or both TNF receptors have yielded conflicting results in that one group reported lack of TNF receptors altered dopamine metabolism and reduced survival of dopaminergic terminals [86]" . . _:b418708985 . _:b418708831 . _:b418708528 . _:b418708984 . _:b418709089 . _:b418708987 . _:b6412237 "levels of cytokines acting in an autocrine manner to potentiate inflammatory responses (e.g., auto-amplification of reactive oxygen species, nitric oxide, and superoxide radicals to form highly oxidizing peroxynitrite species)[7,>>105<<-108]. Given that DA neurons in the midbrain have an inherently elevated oxidative intracellular environment as a result of oxidation reactions required for the synthesis of the neurotransmitter dopamine, chronic neuroinflammation is" . _:b418708506 . _:b418708651 . _:b418708986 . _:b418708545 . _:b418708829 . _:b418708921 . . . . _:b418708695 . _:b418709256 . _:b6412202 . _:b418708969 . _:b418709348 . _:b6412193 "For example, the activation of complement factor C3, the central component of the complement system and a key inflammatory protein may be necessary for plaque clearance by microglia in the AD-afflicted brain [>>56<<,57]. In addition, an important component of any inflammatory response is the activation of anti-inflammatory loops that serve to limit and resolve the initial inflammatory response. The Peroxisome Proliferator-Activated Receptor-\u03B3" . _:b418708965 . . _:b418709311 . . _:b418708514 . . _:b418708546 . . _:b418709202 . _:b6412207 "A\u03B2 vaccinations were also found successful in reducing A\u03B2 levels in two non-human primates, the rhesus monkey [>>68<<] and the Caribbean vervet [69]." . _:b6412212 "Unfortunately, the immunization also resulted in dangerous T-lymphocyte meningoencephalitis in some patients, causing the arrest of these trials [>>70<<,73]. Passive immunization of PDAPP mice peripherally infused with antibodies that recognize aggregated A\u03B2 in neuritic plaques rapidly increased microglial clustering around plaques detectable by in vivo multi-photon microscopy [74] and" . . _:b418709312 . _:b418708938 . _:b418708501 . _:b418708627 . _:b418708500 . _:b418709137 . _:b418709130 . _:b418708503 . _:b418708807 . _:b418708666 . _:b418708502 . _:b418708497 . _:b418708877 . . . _:b418709084 . _:b418708499 . . _:b418708498 . . _:b418708593 . . _:b418708509 . _:b418709344 . _:b418708508 . _:b418708511 . _:b418708510 . . . . _:b418708505 . _:b418708504 . _:b418708746 . _:b418709230 . . _:b418708994 . . _:b418708946 . _:b418708507 . _:b418709317 . _:b418708506 . _:b418708526 . _:b6412206 . _:b418708517 . _:b418709172 . . _:b418708516 . . _:b6412262 "For example, ablating microglial expression of mutant SOD 1 (mSOD1) or transplanting bone marrow from wild-type mice into mSOD1 transgenic mice increases the life span of mutant mice [133,>>134<<], suggesting that SOD1 mutations may indirectly contribute to neuronal death by affecting glial rather than neuronal function." . _:b418708917 . _:b418708519 . . . _:b418708518 . . _:b418709330 . _:b418708513 . _:b6412179 "Transforming Growth Factor-\u03B2 (TGF-\u03B2) cytokine family increases A\u03B2 accumulation in the cerebral blood vessels of mice transgenic for human APP and is upregulated in blood vessels of human patients with Cerebral Amyloid Angiopathy (CAA) [>>40<<]. Co-addition of TGF-\u03B21, 2 and 3 isoforms with A\u03B2 causes increased A\u03B2 accumulation in organotypic hippocampal slices [41]." . _:b6412193 . _:b418708512 . _:b418709378 . _:b6412223 . . _:b418708515 . . _:b418708514 . _:b418708525 . _:b418708961 . . _:b418708524 . . . _:b418709331 . _:b418708527 . . _:b418708526 . _:b418708577 . . _:b418708521 . _:b418708520 . . . _:b418708523 . . _:b418709375 . _:b418708735 . _:b418708718 . _:b418708522 . . _:b418708533 . _:b418708532 . . . . . . _:b6412196 "As such, PPAR\u03B3 activation exerts an anti-inflammatory effect, and PPAR\u03B3 agonists have been shown to inhibit the production of cytokines and pro-inflammatory mediators in response to A\u03B2 [>>58<<]. In addition, there appears to be a feedback signaling loop between A\u03B2 and IL-1\u03B2: A\u03B2 can induce the production of IL-1\u03B2 [7], and the presence of IL-1\u03B2 greatly increases the secretion of cytokines IL-6 and IL-8 in response to A\u03B2 by" . _:b418708535 . _:b418708534 . _:b418708529 . _:b418709050 . _:b6412148 "Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS [>>2<<,3]. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines [4]. While an acute" . _:b418709060 . _:b418708528 . _:b418708932 . _:b6412200 . _:b6412222 . _:b418708531 . _:b418709194 . _:b418708530 . _:b418708601 . _:b418709006 . . _:b418709326 . _:b418708541 . _:b418708540 . _:b418709016 . _:b418708622 . _:b418708543 . . _:b418708542 . . _:b418708537 . _:b418708834 . _:b418709320 . . _:b418708536 . _:b6412153 . . _:b418708741 . _:b418709356 . _:b418708539 . _:b418709150 . _:b418708538 . _:b418709327 . _:b418708549 . _:b6412245 "Once symptoms have manifested, microglial activation correlates with disease severity [>>115<<,116]. In the 3-nitroproprionic acid neurotoxin model of HD in rats, treatment with Celastrol, an anti-inflammatory and antioxidant compound derived from plants, reduced striatal lesion volume [117], indicating that controlling an" . . _:b418709164 . _:b418709095 . _:b418708929 . _:b418708548 . . _:b6412239 . _:b418708551 . _:b418708957 . _:b418708773 . _:b418708550 . _:b418708545 . . _:b418708544 . . _:b6412175 "The bacterial endotoxin lipopolysaccharide (LPS), a powerful inducer of inflammatory responses [>>36<<], exacerbates the appearance and severity of AD pathology in the APPV717F transgenic mouse [37], the APPswe transgenic mouse [38], and the triple-transgenic (3xTgAD) mouse [39]." . _:b418708882 . . _:b418708547 . _:b418709078 . _:b418708546 . _:b6412169 . _:b418708557 . _:b418708554 . _:b418708556 . _:b418708727 . . _:b418709380 . _:b418709033 . _:b6412171 . _:b418708559 . _:b418708870 . . _:b418708558 . . . _:b6412192 . _:b418708553 . . _:b418708552 . . _:b418708555 . _:b418708997 "2"^^ . . _:b418708554 . _:b418708996 "2"^^ . . . _:b418708638 . _:b418708565 . _:b418708999 "2"^^ . _:b418708564 . _:b6412184 . _:b418708998 "2"^^ . . _:b418708567 . _:b418708993 "2"^^ . _:b418708565 . _:b418709213 . _:b418708992 "2"^^ . _:b418708566 . . . . _:b418708995 "2"^^ . . _:b418708561 . _:b6412199 "The ratio of the pro-inflammatory cytokine IL-1\u03B2 to the anti-inflammatory cytokine IL-10 is drastically elevated in the serum of AD patients, giving these patients a definite pro-inflammatory profile [>>60<<]. Increases in levels of IL-1\u03B2 have been correlated with decreases in LTP in the hippocampus, showing that the cytokine itself may impair memory [61]. Other evidence, however, suggests that IL-1\u03B2 may not be driving AD pathogenic processes." . . . _:b418708994 "2"^^ . _:b418708560 . _:b418709109 . . _:b418708563 . _:b418709005 "2"^^ . _:b418708562 . _:b418709004 "2"^^ . . _:b418708573 . _:b418709007 "2"^^ . _:b418708572 . _:b418709006 "2"^^ . _:b418709334 . _:b418708613 . _:b418709140 . . _:b418709001 "2"^^ . _:b418708575 . _:b418708597 . _:b418708594 . _:b418708843 . . _:b418708574 . _:b418709383 . _:b418709000 "2"^^ . . _:b418709155 . _:b418708879 . _:b418708569 . _:b418709003 "2"^^ . _:b418709247 . _:b418708762 . _:b6412269 "In pre-clinical mouse models, certain anti-inflammatory treatments aimed at suppressing microglia activation have been shown to increase the life expectancy of mice expressing human mutant SOD1 by more than 30% [>>140<<]. Anti-inflammatory treatments also prevented neurotoxicity when the CSF of ALS patients was applied to rat spinal cord motor neurons [141]." . _:b418708568 . _:b418709045 . _:b418709002 "2"^^ . _:b418708571 . _:b418709308 . _:b418709013 "2"^^ . _:b418708948 . . _:b418709012 "2"^^ . _:b418708570 . . _:b418708646 . _:b418709015 "2"^^ . _:b418708581 . _:b418708630 . _:b6412192 . _:b418708578 . _:b418709285 . _:b418708580 . _:b418709014 "2"^^ . . _:b418708583 . _:b418709009 "2"^^ . . . _:b418708575 . _:b418709008 "2"^^ . _:b418708582 . _:b418708577 . _:b418709011 "2"^^ . _:b418708751 . _:b418708722 . _:b418708849 . . _:b418708576 . _:b418709010 "2"^^ . _:b418709126 . _:b418709043 . _:b418708579 . _:b418709021 "2"^^ . . _:b418709020 "2"^^ . _:b418708578 . _:b418708589 . _:b418709023 "2"^^ . . . . _:b418708588 . _:b418709022 "2"^^ . _:b418708784 . _:b418708591 . _:b418709017 "2"^^ . _:b418708771 . _:b6412163 . _:b418709016 "2"^^ . _:b418708590 . . _:b6412268 "Importantly, levels of TNF correlate with severity of motor neuron loss in mouse models of the disease [137,138] and both TNF receptors are elevated in the serum of ALS patients [>>139<<]." . . _:b418709019 "2"^^ . _:b418708585 . _:b418708584 . _:b418709018 "2"^^ . . . . _:b418708587 . _:b418709029 "2"^^ . . . . . _:b418709028 "2"^^ . _:b418708586 . _:b418709069 . _:b418708597 . _:b418709031 "2"^^ . _:b6412192 . _:b6412201 . _:b418708596 . _:b418709030 "2"^^ . . _:b418708599 . _:b418709025 "2"^^ . _:b418709005 . _:b418708598 . _:b418709024 "2"^^ . _:b418709377 . _:b418708593 . _:b418709027 "2"^^ . _:b418708592 . _:b418709026 "2"^^ . _:b418708663 . _:b418708595 . _:b418709037 "2"^^ . _:b418708900 . _:b418708777 . _:b418709066 . . . _:b418709036 "2"^^ . _:b418708594 . . _:b6412149 "Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS [2,>>3<<]. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines [4]. While an acute insult" . _:b418708605 . _:b418709039 "2"^^ . . . _:b418709324 . _:b418708604 . _:b418709038 "2"^^ . . _:b418708607 . _:b418709033 "2"^^ . _:b418708982 . _:b6412159 . . _:b418709032 "2"^^ . _:b418708606 . . . _:b418708711 . _:b418709238 . _:b418708601 . _:b418709035 "2"^^ . _:b6412161 . _:b418708974 . . _:b418708600 . _:b418709034 "2"^^ . _:b418708603 . _:b418709045 "2"^^ . _:b418708599 . _:b418709044 "2"^^ . _:b418708602 . _:b6412262 . . _:b418709047 "2"^^ . _:b418708613 . _:b418708612 . _:b418709046 "2"^^ . . _:b418708615 . _:b418709041 "2"^^ . . _:b418708614 . _:b418709040 "2"^^ . _:b6412152 . _:b418708609 . _:b418709043 "2"^^ . . _:b6412169 . _:b418708608 . _:b418709042 "2"^^ . . . _:b418709053 "2"^^ . _:b418708611 . _:b418708828 . _:b418709242 . _:b418708610 . _:b418709052 "2"^^ . _:b418708621 . _:b418709055 "2"^^ . . . _:b6412147 . _:b418708620 . _:b418709054 "2"^^ . . _:b418709187 . _:b418708623 . _:b418709049 "2"^^ . _:b6412170 . . _:b418709048 "2"^^ . _:b418708622 . _:b418708572 . _:b418709196 . _:b418708617 . _:b418709051 "2"^^ . _:b418708616 . _:b418709050 "2"^^ . . _:b418709037 . _:b418708619 . _:b418709061 "2"^^ . . . . _:b418708618 . _:b418709060 "2"^^ . _:b418709001 . _:b418709328 . _:b6412224 . _:b418708629 . _:b418709063 "2"^^ . . _:b418708632 . _:b418708628 . _:b418709062 "2"^^ . . _:b418708623 . _:b418709110 . _:b418709057 "2"^^ . _:b418708631 . _:b418708875 . _:b418709176 . _:b418708630 . _:b418709056 "2"^^ . _:b6412224 "In contrast, studies involving mice deficient in TNF or both TNF receptors have yielded conflicting results in that one group reported lack of TNF receptors altered dopamine metabolism and reduced survival of dopaminergic terminals [>>86<<] and other groups reported TNF-deficient mice to have reduced sensitivity to MPTP-induced neurotoxicity [85,87]." . . _:b418709059 "2"^^ . _:b418708625 . _:b6412186 . _:b418708624 . _:b418709058 "2"^^ . _:b418708842 . _:b418708627 . _:b418709069 "2"^^ . _:b418708883 . _:b418708626 . _:b418709068 "2"^^ . _:b418708540 . _:b418708637 . _:b418709246 . _:b418709071 "2"^^ . . _:b418708636 . _:b418709070 "2"^^ . . _:b418708559 . _:b418708619 . _:b418709065 "2"^^ . _:b418709002 . _:b418708639 . _:b418708638 . _:b418709064 "2"^^ . . . _:b418708633 . _:b418709197 . _:b418709067 "2"^^ . _:b418708760 . _:b418709066 "2"^^ . _:b418708632 . . _:b418709103 . _:b418708635 . _:b6412162 "Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [18] and since then, the association between neuroinflammation and AD has been extensively investigated [7,19-24] and reviewed [>>19<<,25]. Human microglia display an activated phenotype when they surround plaques [23] that includes upregulation of Human Leukocyte Antigen-DR (HLA-DR) [18]. In addition to producing cytokines and other pro-inflammatory mediators [19,26]," . _:b418709077 "2"^^ . _:b418708634 . _:b418709076 "2"^^ . . _:b418708645 . _:b418709079 "2"^^ . . . . _:b418709360 . _:b418709195 . _:b418709078 "2"^^ . _:b418708644 . _:b6412154 "microglia activation: convergence point for diverse stimuli that compromise neuronal survival" . . . . _:b418708647 . _:b418709275 . _:b418709073 "2"^^ . . _:b418708646 . _:b418709072 "2"^^ . _:b418709041 . _:b418708641 . _:b418709075 "2"^^ . . . . _:b418709074 "2"^^ . _:b418708640 . . _:b418708778 . _:b418709298 . _:b6412202 "In addition, IL-1\u03B2 was recently shown to upregulate the \u03B1-secretase TACE, thus increasing non-amyloidogenic cleavage of APP and decreasing A\u03B2 production [>>63<<]. Therefore, while it may participate in neuroinflammatory responses in AD brain by activating microglia to secrete other inflammatory mediators, IL-1\u03B2 is not required to drive A\u03B2 deposition and may in fact activate non-amyloidogenic" . _:b418708643 . _:b6412270 "Anti-inflammatory treatments also prevented neurotoxicity when the CSF of ALS patients was applied to rat spinal cord motor neurons [>>141<<]. Although a generalized neuroinflammatory response may be driving progressive loss of motor neurons, not all inflammatory mediators have been strongly implicated in ALS. For instance, IL-1\u03B2 may not be critical to ALS pathogenesis as" . _:b418709085 "2"^^ . . . . _:b418709084 "2"^^ . _:b418708642 . . _:b418708904 . _:b418708656 . _:b418709087 "2"^^ . _:b418709000 . _:b418708653 . _:b418708652 . _:b418709086 "2"^^ . . _:b418709316 . _:b418708655 . _:b418709081 "2"^^ . . _:b418708852 . . _:b418708654 . _:b418709080 "2"^^ . _:b418709030 . . . _:b418709083 "2"^^ . _:b418708649 . . _:b418708980 . _:b418708648 . _:b418709163 . _:b418709082 "2"^^ . . _:b418708651 . _:b418709093 "2"^^ . . _:b418708610 . _:b418709092 "2"^^ . _:b418708664 . _:b418708650 . . _:b418708661 . _:b418709095 "2"^^ . _:b418708660 . _:b418709094 "2"^^ . . _:b418708663 . _:b418709089 "2"^^ . . . _:b418708662 . _:b418709088 "2"^^ . _:b418708657 . _:b418709091 "2"^^ . _:b418708656 . _:b418709198 . _:b418709090 "2"^^ . . . _:b418708659 . _:b418709101 "2"^^ . . _:b418709271 . . _:b418708658 . _:b418709100 "2"^^ . . . _:b418708669 . _:b418709103 "2"^^ . . . . _:b418708516 . _:b418709102 "2"^^ . _:b418708668 . _:b418708824 . _:b418709269 . _:b6412160 "Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [18] and since then, the association between neuroinflammation and AD has been extensively investigated [>>7<<,19-24] and reviewed [19,25]." . _:b418708671 . _:b418709097 "2"^^ . . _:b418708705 . _:b418708670 . _:b418709096 "2"^^ . _:b6412247 "In the 3-nitroproprionic acid neurotoxin model of HD in rats, treatment with Celastrol, an anti-inflammatory and antioxidant compound derived from plants, reduced striatal lesion volume [>>117<<], indicating that controlling an inflammatory response could be therapeutically beneficial as HD progresses." . _:b6412172 "Since microglia are found in large numbers around neuritic amyloid plaques, but not diffuse in human AD patients, and in mice transgenic for mutant APP [>>33<<], it has been postulated that microglia play a role in the conversion of diffuse to neuritic senile plaques but not in the origin of diffuse plaques [34]." . _:b418709376 . _:b6412219 . . _:b418709099 "2"^^ . _:b418708665 . _:b6412241 "Increases in labeling of complement proteins in neurons and astrocytes and a 2-5 fold increase in activators and regulators of the classical complement pathway have also been detected in human HD brains by RT-PCR [>>112<<]. Lastly, clinical plasma samples from HD gene carriers contain increased levels of pro-inflammatory cytokines involved in the innate immune response, such as IL-6 [113]." . _:b418708664 . _:b418709098 "2"^^ . _:b418709067 . _:b418708561 . _:b418709109 "2"^^ . _:b418708667 . _:b418708666 . _:b418709108 "2"^^ . _:b418709173 . _:b418709288 . _:b6412191 . . _:b418709111 "2"^^ . _:b418708677 . _:b418708661 . _:b418709151 . _:b418708676 . _:b418709110 "2"^^ . . . . _:b418709105 "2"^^ . _:b418708679 . . _:b418709104 "2"^^ . _:b418708678 . . . . . . _:b418709107 "2"^^ . _:b418708673 . _:b418708662 . . _:b418709009 . . _:b418709106 "2"^^ . _:b418708998 . _:b418708672 . _:b418708675 . _:b418709117 "2"^^ . _:b418708674 . _:b418709116 "2"^^ . _:b418708685 . _:b418709119 "2"^^ . _:b418708684 . _:b418709118 "2"^^ . . . _:b418708498 . _:b418709244 . . _:b418709113 "2"^^ . _:b418708687 . _:b418708686 . _:b418709112 "2"^^ . . . _:b418708681 . _:b418709115 "2"^^ . _:b418708776 . _:b418708680 . _:b418709114 "2"^^ . . _:b418708683 . _:b418709319 . _:b418709125 "2"^^ . _:b418708618 . _:b418709081 . _:b418708682 . _:b418709124 "2"^^ . . _:b418709127 "2"^^ . _:b418708693 . _:b418709209 . _:b6412228 . _:b418708987 . _:b418708692 . _:b418709126 "2"^^ . _:b418708861 . _:b418708956 . . _:b6412216 . _:b418708695 . _:b418709121 "2"^^ . _:b418708669 . _:b418709167 . . _:b418708694 . _:b418709120 "2"^^ . . _:b418708689 . _:b418709123 "2"^^ . _:b418708688 . _:b418709122 "2"^^ . _:b418709101 . . _:b418708691 . _:b418709133 "2"^^ . _:b418709228 . . _:b418708690 . _:b418709132 "2"^^ . _:b418708701 . _:b418709135 "2"^^ . _:b418708700 . _:b418709134 "2"^^ . _:b418709061 . _:b418708703 . _:b418709129 "2"^^ . . _:b418708702 . _:b418709128 "2"^^ . _:b418709127 . _:b418708752 . _:b418708697 . _:b418709131 "2"^^ . . _:b418708636 . _:b418708696 . _:b418709130 "2"^^ . . . _:b418708699 . _:b418709141 "2"^^ . _:b418708637 . . . _:b418708698 . _:b418709140 "2"^^ . . . . _:b418709143 "2"^^ . _:b418708709 . _:b6412253 "Areas where degenerating motor neurons are present in both ALS patients and mouse models are marked by the presence of cytokines and immune cells, including T cells, activated microglia, and astrocytes [121,>>122<<]. In addition PET imaging of ALS patients showed an increase in activated microglia in the motor cortex that correlates with upper motor neuron symptoms [123]. In some ALS disease models the presence of immune cells precedes the disease" . _:b418708708 . _:b418709142 "2"^^ . . _:b418709361 . _:b418708711 . _:b418709137 "2"^^ . . . _:b418708838 . _:b418708710 . _:b6412167 . _:b418709136 "2"^^ . . . _:b418709139 "2"^^ . _:b418708705 . . _:b418708704 . _:b418709138 "2"^^ . _:b418708707 . _:b418709149 "2"^^ . _:b418708706 . _:b418709148 "2"^^ . _:b418708555 . _:b418708558 . _:b418708892 . _:b418708717 . _:b418709151 "2"^^ . _:b418709219 . _:b6412260 "Nevertheless, several studies have suggested that SOD1 mutations in neurons alone are insufficient to cause ALS and that dysfunction in support glia may contribute to disease development and progression [>>129<<-132]. For example, ablating microglial expression of mutant SOD 1 (mSOD1) or transplanting bone marrow from wild-type mice into mSOD1 transgenic mice increases the life span of mutant mice [133,134], suggesting that SOD1 mutations may" . _:b418708716 . _:b418709158 . _:b418709150 "2"^^ . . _:b418708794 . . _:b418709145 "2"^^ . _:b418708719 . _:b6412191 "mice reduced the number and area of amyloid plaques, as well as the numbers of activated microglia [51], and administration of R-flurbiprofen rescued deficits in hippocampal and medial temporal lobe-dependent memory and learning [>>52<<]. However, thus far, clinical trials using systemic administration of NSAIDs have yielded mixed or inconclusive results [53-55], reflecting the need to identify and target the key inflammatory mediators that promote amyloid-associated" . _:b418708718 . _:b418709144 "2"^^ . . _:b6412210 . _:b418709147 "2"^^ . _:b418708713 . . _:b418708712 . _:b6412165 "Human microglia display an activated phenotype when they surround plaques [23] that includes upregulation of Human Leukocyte Antigen-DR (HLA-DR) [>>18<<]. In addition to producing cytokines and other pro-inflammatory mediators [19,26], microglia have also been reported to exert toxicity on neurons that have been pre-exposed to low concentrations of A\u03B242 via a CD14-dependent process [27]." . _:b418709146 "2"^^ . _:b418708895 . . . . _:b418709157 "2"^^ . _:b418708715 . _:b418709220 . . _:b418709206 . _:b418708534 . _:b418709156 "2"^^ . _:b418708714 . . _:b418708725 . _:b418709159 "2"^^ . _:b418708729 . _:b6412165 . . _:b418708724 . _:b418709158 "2"^^ . _:b418708712 . _:b418708727 . _:b418709153 "2"^^ . _:b418709208 . _:b418708726 . _:b418709152 "2"^^ . _:b418708721 . _:b418709155 "2"^^ . _:b418709025 . _:b418708720 . _:b418709154 "2"^^ . _:b6412154 . . _:b418708723 . _:b418709165 "2"^^ . _:b418709134 . _:b6412157 . _:b418708722 . _:b418709164 "2"^^ . _:b418709225 . _:b6412146 . _:b418708787 . _:b418708733 . _:b418709167 "2"^^ . _:b418709257 . . _:b418709166 "2"^^ . _:b418708732 . _:b418709261 . _:b418709345 . . _:b418709161 "2"^^ . _:b418708735 . . . _:b418708734 . _:b418709160 "2"^^ . . . _:b418709163 "2"^^ . _:b418708729 . _:b418709189 . _:b418708728 . _:b418709162 "2"^^ . _:b418708731 . _:b418709173 "2"^^ . _:b418709091 . _:b418708730 . _:b418709172 "2"^^ . _:b6412263 "Consistent with this idea, mSOD1 mice stimulated with LPS secrete more inflammatory mediators, including TNF [>>135<<], MCP-1, TGF-\u03B2[121] and IFN-\u03B3 [136], than control mice." . _:b6412209 "A clinical trial of A\u03B242 vaccinations was undertaken by Elan Pharmaceuticals in AD patients, and the immunizations resulted in significant clearance of A\u03B2 and plaque removal in some of the patients [>>70<<,71], as well as a slowing of the cognitive decline in patients who produced antibodies against the peptide [72]." . _:b418709175 "2"^^ . _:b6412164 . . . _:b418709174 "2"^^ . _:b6412221 . _:b418709181 . _:b418709169 "2"^^ . . _:b418709168 "2"^^ . _:b6412161 . . _:b418708750 . _:b418709171 "2"^^ . . _:b418709170 "2"^^ . _:b418709192 . . _:b418708699 . _:b418708633 . _:b418708925 . _:b418709181 "2"^^ . . _:b418709180 "2"^^ . _:b418709076 . . _:b418709183 "2"^^ . . . _:b418709182 "2"^^ . . _:b418709252 . _:b418708803 . _:b418709313 . _:b418709177 "2"^^ . _:b418709176 "2"^^ . _:b418709179 "2"^^ . . . _:b6412257 . . _:b418709178 "2"^^ . . _:b418709189 "2"^^ . _:b418709080 . . _:b418709188 "2"^^ . _:b418708726 . _:b418709300 . . _:b418709191 "2"^^ . _:b418709153 . _:b418708733 . _:b418709190 "2"^^ . . _:b418709289 . _:b6412174 . . _:b418709185 "2"^^ . _:b418709107 . _:b6412239 "The R6/2 mouse model of HD displays increased serum levels of IL-6 and in downstream IL-6 effectors, such as alpha-2-macroglobulin (A2 M) and complement components [>>110<<]. In the CNS, microarray profiling of several brain regions from HD patients and controls revealed increased gliosis and expression of inflammation-related genes, including GFAP and complement proteins. Increases were most pronounced in" . _:b418709183 . _:b6412258 . _:b418709184 "2"^^ . . _:b418709187 "2"^^ . . . _:b418709186 "2"^^ . . _:b418708911 . . . _:b418709197 "2"^^ . _:b418708896 . _:b418708688 . _:b418709196 "2"^^ . _:b418709199 "2"^^ . . _:b6412185 "Not only is neuroinflammation believed to be one of the earliest consequences of A\u03B2 deposition, it has been shown to accelerate neurodegeneration and contribute to progression of pathology [>>46<<]. Epidemiological studies suggest a link between chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and reduced risk for AD." . _:b418709365 . _:b418709198 "2"^^ . _:b418709272 . . _:b418709379 . . _:b418709193 "2"^^ . _:b418708817 . _:b418709192 "2"^^ . _:b418708908 . _:b418709195 "2"^^ . _:b6412161 . . _:b418708815 . _:b418709194 "2"^^ . _:b418708847 . _:b6412238 . _:b418709205 "2"^^ . . _:b418708497 . _:b418709204 "2"^^ . . _:b418709207 "2"^^ . . _:b418709206 "2"^^ . _:b418708781 . . . _:b418709201 "2"^^ . . _:b418709200 "2"^^ . _:b418708589 . _:b418709203 "2"^^ . . _:b418709202 "2"^^ . . . . . _:b418709213 "2"^^ . _:b418708775 . _:b6412250 "found in glial nuclei where it can act to alter gene expression, probably because of its aberrant interactions with transcription factors that are made possible by glutamine expansion-related conformational changes in the htt protein [>>119<<]. Interestingly, mutant, but not normal htt activates the IKK complex, the major kinase that leads to phosphorylation-induced degradation of I\u03BABs, leading to increased translocation of NF-\u03BAB dimers to the nucleus in mouse striatal cells" . . _:b418709212 "2"^^ . . _:b418708676 . _:b418709215 "2"^^ . . _:b418709214 "2"^^ . . _:b418709209 "2"^^ . _:b418709208 "2"^^ . _:b418709211 "2"^^ . _:b418709053 . . _:b418709210 "2"^^ . _:b418708734 . . _:b418709237 . _:b418708768 . _:b418709221 "2"^^ . _:b418709220 "2"^^ . _:b418708890 . _:b418709223 "2"^^ . _:b418709222 "2"^^ . _:b6412266 "Importantly, levels of TNF correlate with severity of motor neuron loss in mouse models of the disease [>>137<<,138] and both TNF receptors are elevated in the serum of ALS patients [139]." . _:b418709217 "2"^^ . _:b6412260 . . _:b418708941 . _:b418709216 "2"^^ . . _:b418709382 . _:b418709219 "2"^^ . _:b6412198 . . _:b418709218 "2"^^ . _:b418708818 . . . _:b6412230 . _:b418709229 "2"^^ . . _:b418709228 "2"^^ . . _:b418709304 . _:b418708698 . _:b418708826 . _:b418708643 . _:b6412172 . _:b418709231 "2"^^ . . _:b418709230 "2"^^ . _:b418709010 . . _:b418709225 "2"^^ . . _:b418709160 . _:b418709224 "2"^^ . . _:b418709227 "2"^^ . _:b418709226 "2"^^ . _:b418708548 . _:b418709090 . _:b418709237 "2"^^ . _:b6412229 "Most importantly, chronic infusion of dominant negative TNF inhibitor proteins into SNpc of adult rats protected nigral DA neurons from LPS and 6-OHDA induced degeneration [>>91<<] as did a single nigral injection of a lentivirus encoding DN-TNF in 6-OHDA hemiparkinsonian rats [92]." . _:b418708975 . _:b418709236 "2"^^ . _:b418708686 . _:b6412247 . _:b418709239 "2"^^ . _:b418708709 . . _:b418709238 "2"^^ . . . _:b418709233 "2"^^ . _:b6412156 "Persistent activation of brain-resident microglia may increase the permeability of the BBB and promote increased infiltration of peripheral macrophages, the phenotype of which is critically determined by the CNS environment [>>10<<]." . _:b418709232 "2"^^ . _:b418708615 . _:b6412230 "dominant negative TNF inhibitor proteins into SNpc of adult rats protected nigral DA neurons from LPS and 6-OHDA induced degeneration [91] as did a single nigral injection of a lentivirus encoding DN-TNF in 6-OHDA hemiparkinsonian rats [>>92<<]. Given that TNF receptors are expressed in nigrostriatal dopamine neurons [93,94] and these neurons are selectively vulnerable to TNF-induced toxicity [95-99], these early genetic studies and the more recent chronic inflammation models" . _:b418709235 "2"^^ . . . _:b418709234 "2"^^ . . _:b418709245 "2"^^ . _:b6412220 . . _:b418709244 "2"^^ . _:b418709247 "2"^^ . _:b6412252 . _:b418709301 . _:b418708715 . . . _:b418709254 . _:b418709246 "2"^^ . _:b418709166 . . _:b418709241 "2"^^ . . . _:b418709240 "2"^^ . _:b6412228 "In the second model exposure of pregnant rats to LPS and thus, in utero exposure of embryos to the endotoxin, caused a loss of DA neurons in postnatal brains [>>90<<]. Most importantly, chronic infusion of dominant negative TNF inhibitor proteins into SNpc of adult rats protected nigral DA neurons from LPS and 6-OHDA induced degeneration [91] as did a single nigral injection of a lentivirus encoding" . _:b418709243 "2"^^ . _:b418709242 "2"^^ . _:b418709253 "2"^^ . _:b6412203 . _:b418708650 . _:b418709252 "2"^^ . . . . _:b418709255 "2"^^ . . . _:b418709051 . . . _:b418709254 "2"^^ . . . _:b6412153 . . _:b418709249 "2"^^ . . . _:b6412237 . _:b418709359 . . _:b418709248 "2"^^ . _:b418709251 "2"^^ . _:b6412264 . _:b418709250 "2"^^ . _:b418708893 . _:b418709261 "2"^^ . . _:b418708691 . _:b418709260 "2"^^ . . _:b418709104 . _:b418709263 "2"^^ . . _:b418708959 . _:b418709262 "2"^^ . _:b418709257 "2"^^ . _:b418709256 "2"^^ . _:b418709259 "2"^^ . _:b418709258 "2"^^ . _:b418709136 . _:b418708716 . _:b418708677 . _:b418708823 . . . _:b418709269 "2"^^ . _:b418708924 . . _:b418709268 "2"^^ . _:b418709271 "2"^^ . _:b418709108 . _:b418709270 "2"^^ . _:b418708520 . _:b418708704 . _:b418708702 . _:b418709265 "2"^^ . _:b418709087 . _:b6412207 . . . _:b418709264 "2"^^ . _:b418708551 . _:b418708710 . _:b418709267 "2"^^ . _:b418709266 "2"^^ . _:b6412249 "Microglia from YAC128 and R6/2 mouse models of HD respond in a similar overactive manner [>>113<<]. Mutant htt is found in glial nuclei where it can act to alter gene expression, probably because of its aberrant interactions with transcription factors that are made possible by glutamine expansion-related conformational changes in the" . _:b6412231 . _:b418708805 . _:b418709277 "2"^^ . _:b6412155 "In the presence of an activating stimulus, microglial cell-surface receptor expression is modified and the cells change from a monitoring role to one of protection and repair (reviewed in [>>4<<,9]). In addition to up-regulation of the key surface receptors mentioned above, there is up-regulation of proteins such as CD1, lymphocyte function-associated antigen 1 (LFA-1), intercellular adhesion molecule 1 (ICAM-1 or CD54), and" . _:b418709276 "2"^^ . _:b418709279 "2"^^ . _:b6412242 "Lastly, clinical plasma samples from HD gene carriers contain increased levels of pro-inflammatory cytokines involved in the innate immune response, such as IL-6 [>>113<<]." . _:b418709278 "2"^^ . _:b418709273 "2"^^ . _:b6412183 "Serum levels of the acute phase protein \u03B11-antichymotrypsin, which is upregulated by injury, trauma and infection, are also significantly higher in AD patients than healthy controls [>>44<<]. And clinically, a proteomic study of plasma from control subjects, patients with Mild Cognitive Impairment (MCI) and patients with AD suggested that dysregulated systemic immune responses are present in patients who progress from MCI" . _:b418709272 "2"^^ . _:b418708785 . _:b418709216 . _:b418708951 . _:b418709275 "2"^^ . _:b418709274 "2"^^ . _:b418709285 "2"^^ . . . _:b418709284 "2"^^ . _:b418709287 "2"^^ . _:b418709286 "2"^^ . _:b418709281 "2"^^ . _:b418709190 . . . _:b418709280 "2"^^ . _:b418709283 "2"^^ . _:b418708536 . . _:b418709282 "2"^^ . . . _:b418709293 "2"^^ . . _:b418708967 . _:b6412233 "Given that TNF receptors are expressed in nigrostriatal dopamine neurons [93,94] and these neurons are selectively vulnerable to TNF-induced toxicity [>>95<<-99], these early genetic studies and the more recent chronic inflammation models of PD strongly implicate TNF and its downstream targets in neurotoxin- and endotoxin-induced loss of nigral DA neurons." . _:b418709292 "2"^^ . _:b6412161 . _:b418709295 "2"^^ . _:b6412218 . . _:b6412153 . . _:b418709039 . _:b418709096 . _:b418709294 "2"^^ . _:b418708848 . . _:b418709289 "2"^^ . _:b418708979 . . . _:b418709288 "2"^^ . _:b418708968 . _:b418708765 . _:b418709291 "2"^^ . _:b6412217 . . _:b418709290 "2"^^ . _:b418709042 . . _:b6412246 . _:b418709182 . . _:b418709235 . _:b6412219 "body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem and a classic motor phenotype resulting from substantial loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc) (reviewed in [>>79<<]). A number of studies have confirmed the presence of inflammatory mediators (including TNF, IL-1\u03B2, IL-6, and IFN\u03B3) in the cerebrospinal fluid (CSF) of patients with PD as well as in the post-mortem SNpc in PD patient brains [80-84]." . _:b418709301 "2"^^ . _:b418709300 "2"^^ . . _:b418709303 "2"^^ . _:b418708692 . _:b418708939 . . _:b418709302 "2"^^ . . _:b418708872 . _:b418709297 "2"^^ . _:b418708653 . _:b6412189 "Most recently in what is the largest and longest duration epidemiological study to date, long-term (> 5 yrs) NSAID use, in particular ibuprofen, was shown to be protective against development of AD [>>50<<]. These findings suggest that the protection afforded by chronic NSAID use in the studies of AD patients may in part be derived by attenuation of microglia activation. Consistent with the epidemiological findings on ibuprofen, chronic" . _:b418709296 "2"^^ . _:b418709299 "2"^^ . . . _:b418709298 "2"^^ . . _:b418709309 "2"^^ . _:b418708693 . _:b418709308 "2"^^ . _:b418709311 "2"^^ . _:b418709310 "2"^^ . _:b418708789 . _:b418709305 "2"^^ . _:b418709364 . _:b418709304 "2"^^ . . . _:b418709307 "2"^^ . _:b418708947 . _:b418709113 . . _:b418709306 "2"^^ . _:b418708617 . _:b418709317 "2"^^ . . . _:b418709316 "2"^^ . _:b6412261 "For example, ablating microglial expression of mutant SOD 1 (mSOD1) or transplanting bone marrow from wild-type mice into mSOD1 transgenic mice increases the life span of mutant mice [>>133<<,134], suggesting that SOD1 mutations may indirectly contribute to neuronal death by affecting glial rather than neuronal function." . _:b418708977 . _:b418709319 "2"^^ . . . _:b418709318 "2"^^ . . . _:b418709313 "2"^^ . _:b418708576 . . _:b418709312 "2"^^ . _:b418708927 . _:b418709315 "2"^^ . . _:b418709314 "2"^^ . . . _:b418709325 "2"^^ . . _:b418708671 . _:b418709114 . _:b418709324 "2"^^ . _:b418708586 . . _:b418709327 "2"^^ . . _:b418708721 . _:b418709326 "2"^^ . . _:b418708511 . _:b418709321 "2"^^ . _:b418709320 "2"^^ . _:b418708660 . _:b418709323 "2"^^ . . _:b418709149 . . _:b418709322 "2"^^ . . _:b418709333 "2"^^ . . _:b418709332 "2"^^ . _:b418709058 . _:b418709092 . _:b418709335 "2"^^ . . _:b418708990 . _:b418709334 "2"^^ . . _:b418708697 . _:b418709329 "2"^^ . _:b6412158 . _:b418708940 . _:b6412269 . _:b418709328 "2"^^ . . . . _:b418709331 "2"^^ . . _:b418709330 "2"^^ . _:b6412162 . . . _:b418709341 "2"^^ . _:b418709117 . _:b418709340 "2"^^ . . _:b418709343 "2"^^ . _:b6412161 . . . _:b6412166 . _:b418709342 "2"^^ . . . . . _:b418709337 "2"^^ . . . _:b418709321 . _:b418708694 . _:b418709336 "2"^^ . _:b6412217 "In addition, there is strong evidence that using shorter A\u03B2 peptides is safer than using full-length A\u03B240 or 42 as the immunogen [>>77<<]. In short, A\u03B2 immunotherapy holds promise but will need to be made safer and more effective in its ability to generate good antibody titers in the elderly [78]. If these novel immunogens can enhance A\u03B2 antibody generation without the" . . _:b418709339 "2"^^ . . . _:b418709338 "2"^^ . _:b6412147 "brain barrier (BBB), it is now clear that while peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults [>>1<<]. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS [2,3]." . _:b6412192 "However, thus far, clinical trials using systemic administration of NSAIDs have yielded mixed or inconclusive results [>>53<<-55], reflecting the need to identify and target the key inflammatory mediators that promote amyloid-associated neuropathology." . . . . _:b418709349 "2"^^ . _:b6412150 . _:b418709348 "2"^^ . _:b6412151 . _:b418709162 . _:b6412216 "Administration of antibodies specifically directed against oligomers of A\u03B2 improved learning and memory in Tg2576 mice [>>76<<]. Therefore, passive immunization may be a safer approach in AD patients. In addition, there is strong evidence that using shorter A\u03B2 peptides is safer than using full-length A\u03B240 or 42 as the immunogen [77]. In short, A\u03B2 immunotherapy" . . _:b6412213 "Unfortunately, the immunization also resulted in dangerous T-lymphocyte meningoencephalitis in some patients, causing the arrest of these trials [70,>>73<<]. Passive immunization of PDAPP mice peripherally infused with antibodies that recognize aggregated A\u03B2 in neuritic plaques rapidly increased microglial clustering around plaques detectable by in vivo multi-photon microscopy [74] and" . _:b418709351 "2"^^ . . _:b418709013 . . . _:b418709350 "2"^^ . . _:b418709345 "2"^^ . _:b418708717 . _:b418709344 "2"^^ . _:b6412155 . _:b6412177 . _:b418708822 . _:b418709347 "2"^^ . _:b418709346 "2"^^ . _:b418709026 . _:b418709357 "2"^^ . . . _:b418709356 "2"^^ . _:b418709318 . _:b418709359 "2"^^ . _:b6412248 "However, treatment with acetylsalicylate or rofecoxib, anti-inflammatory drugs commonly used in the clinic, was not neuroprotective in either the R6/2 or N171-82Q transgenic mouse models of HD [>>118<<]." . . _:b418708935 . _:b418708866 . . _:b418709358 "2"^^ . _:b418709231 . _:b418708973 . _:b418709353 "2"^^ . _:b418709352 "2"^^ . . . _:b418708880 . _:b418709355 "2"^^ . _:b418709354 "2"^^ . . _:b418709365 "2"^^ . . _:b418709068 . . _:b418709364 "2"^^ . . _:b418709367 "2"^^ . _:b418708547 . . _:b418709366 "2"^^ . _:b418709203 . _:b418709361 "2"^^ . _:b418708659 . _:b6412248 . _:b418708791 . _:b418709360 "2"^^ . . _:b418709363 "2"^^ . _:b418709362 "2"^^ . _:b418708864 . _:b418708703 . _:b418709373 "2"^^ . _:b6412241 . _:b418708871 . _:b418709372 "2"^^ . _:b418709017 . _:b418709375 "2"^^ . . _:b418709358 . _:b418709374 "2"^^ . _:b418708901 . _:b418709369 "2"^^ . _:b418709368 "2"^^ . . _:b418709371 "2"^^ . . _:b418709370 "2"^^ . _:b418709381 "2"^^ . _:b418709380 "2"^^ . _:b418709383 "2"^^ . _:b418708605 . _:b418708678 . . _:b418709382 "2"^^ . _:b418708607 . _:b418708922 . _:b418708616 . _:b418709377 "2"^^ . _:b418709376 "2"^^ . . _:b418709379 "2"^^ . _:b418709337 . _:b418709378 "2"^^ . . . _:b418708869 . _:b418708530 . _:b418708731 . . . _:b6412267 "Importantly, levels of TNF correlate with severity of motor neuron loss in mouse models of the disease [137,>>138<<] and both TNF receptors are elevated in the serum of ALS patients [139]." . _:b418709384 "2"^^ . _:b418708832 . . _:b418709253 . . _:b418709252 . _:b418708926 . _:b418708839 . . _:b418709094 . _:b418709295 . _:b418708689 . _:b418708550 . _:b418709255 . . . _:b418709254 . . _:b418709161 . _:b418709249 . . _:b418709248 . . . _:b418709251 . _:b6412180 . _:b418709250 . _:b418709201 . _:b418709261 . _:b418708928 . . _:b418709260 . _:b6412163 "Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [18] and since then, the association between neuroinflammation and AD has been extensively investigated [7,19-24] and reviewed [19,>>25<<]. Human microglia display an activated phenotype when they surround plaques [23] that includes upregulation of Human Leukocyte Antigen-DR (HLA-DR) [18]. In addition to producing cytokines and other pro-inflammatory mediators [19,26]," . _:b418708804 . _:b6412196 . _:b418708850 . _:b418709263 . _:b418708645 . _:b418709262 . . _:b418709257 . . _:b418708674 . . . _:b418709256 . _:b418708810 . _:b6412234 "These polymorphisms are over-represented in specific cohorts of individuals affected with PD and may confer increased susceptibility for the disease [>>100<<-104]. However, most of these findings have not been replicated in independent studies and a meta-analysis of multiple association studies is needed to assess the overall genetic effect of cytokine gene polymorphisms on neurodegenerative" . _:b418709259 . . _:b6412234 . _:b418709258 . _:b418709269 . _:b418709268 . _:b6412171 "Moreover, numbers of IL-1\u03B1 positive (i.e., pro-inflammatory) microglia are increased in the cortical layers affected by plaque pathology in AD patients [>>32<<]. Since microglia are found in large numbers around neuritic amyloid plaques, but not diffuse in human AD patients, and in mice transgenic for mutant APP [33], it has been postulated that microglia play a role in the conversion of diffuse" . _:b418708668 . . _:b418709121 . _:b418709271 . . _:b418709270 . _:b418708983 . _:b418709265 . _:b418709264 . . _:b418709267 . _:b418709266 . _:b418709277 . . _:b418709276 . . . _:b418708825 . _:b418708588 . _:b418708504 . _:b418709279 . . . . _:b418709278 . . . _:b418708936 . _:b418709273 . . _:b418709272 . _:b418708591 . _:b418708631 . _:b418709275 . _:b418709274 . _:b418709286 . . . _:b418709285 . . _:b6412149 . _:b418709284 . _:b418709148 . . _:b418709287 . _:b418708856 . _:b6412188 "NSAIDs chronically with that of cognitively normal patients who did not use NSAIDs revealed no changes in the appearance of senile plaques, but a 3-fold decrease in the number of activated microglia in the brains of chronic NSAID users [>>49<<]. Most recently in what is the largest and longest duration epidemiological study to date, long-term (> 5 yrs) NSAID use, in particular ibuprofen, was shown to be protective against development of AD [50]." . _:b418709129 . _:b418709283 . _:b418709191 . _:b6412271 . _:b418709286 . . . _:b418708783 . _:b418709281 . _:b418708907 . _:b418709280 . _:b418709283 . . _:b418708740 . _:b418708742 . _:b418709282 . _:b418709047 . _:b418709185 . _:b418709293 . _:b418709332 . _:b418708888 . _:b418709292 . . _:b418709295 . _:b418708988 . . _:b418709294 . _:b418708885 . _:b418709289 . . _:b418709288 . . _:b418709222 . . . _:b418708978 . _:b418709291 . _:b6412261 . _:b418709290 . _:b418708728 . . . _:b418709301 . _:b418709300 . _:b418708862 . _:b6412158 . _:b418709303 . . _:b418709302 . _:b418708739 . . _:b418709297 . _:b6412150 "This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines [>>4<<]. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. Therefore, it is believed that an acute neuroinflammatory response is" . _:b418709296 . . _:b6412257 "In some ALS disease models the presence of immune cells precedes the disease phenotype [124], and the chemokine MCP-1, a potent chemotactic stimulus for microglia [125] is elevated in the CSF of ALS patients [>>126<<], suggesting that neuroinflammation could contribute to disease progression." . . _:b418709299 . _:b418708672 . _:b418709354 . _:b6412213 . . _:b418709298 . . _:b418708560 . _:b418709309 . _:b418708780 . _:b418708999 . . _:b418709308 . _:b418708799 . _:b418708759 . _:b418709293 . . _:b418709311 . . _:b418708966 . _:b418709310 . _:b418709105 . . _:b418709305 . _:b418709267 . _:b418709304 . . . _:b418709032 . _:b418709307 . _:b418709306 . . _:b6412214 "Passive immunization of PDAPP mice peripherally infused with antibodies that recognize aggregated A\u03B2 in neuritic plaques rapidly increased microglial clustering around plaques detectable by in vivo multi-photon microscopy [>>74<<] and reduced plaque burden and AD pathology in PDAPP mice [75]." . _:b6412161 "Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [18] and since then, the association between neuroinflammation and AD has been extensively investigated [7,>>19<<-24] and reviewed [19,25]." . . _:b418709317 . _:b418708508 . _:b418709316 . . . . . _:b418709319 . . _:b418709260 . . _:b418709318 . _:b418708525 . _:b418708884 . _:b418708758 . _:b418709313 . _:b418709312 . _:b418709281 . _:b418709315 . . _:b418709236 . _:b418708529 . _:b418709314 . _:b6412190 "Consistent with the epidemiological findings on ibuprofen, chronic ibuprofen administration in aged transgenic mice reduced the number and area of amyloid plaques, as well as the numbers of activated microglia [>>51<<], and administration of R-flurbiprofen rescued deficits in hippocampal and medial temporal lobe-dependent memory and learning [52]." . _:b6412255 "In some ALS disease models the presence of immune cells precedes the disease phenotype [>>124<<], and the chemokine MCP-1, a potent chemotactic stimulus for microglia [125] is elevated in the CSF of ALS patients [126], suggesting that neuroinflammation could contribute to disease progression." . _:b418709325 . . _:b6412259 "While multiple genetic loci have been identified as causal in familial forms of ALS, 20% of familial cases involve a gain of function mutation in Cu/Zn superoxide dismutase I (SOD1) [>>128<<]. In addition to the well-established role of SOD1 as a critical anti-oxidant enzyme, evidence suggests that part of its normal function is to protect against protein aggregation, a phenomenon that is known to hasten neuronal degeneration." . _:b418708868 . . _:b418709324 . _:b418709036 . . . _:b418709327 . _:b418708606 . _:b418709035 . _:b6412158 . _:b418708667 . _:b418709326 . _:b418708984 . _:b418709321 . _:b418709320 . . _:b418709323 . _:b418708708 . _:b418708857 . . . _:b418709322 . _:b418709333 . . . _:b418709332 . . _:b418708923 . _:b418708960 . _:b418708569 . _:b418709335 . _:b418709334 . _:b418708675 . _:b418709004 . _:b418709362 . _:b418709329 . _:b418708681 . _:b418709328 . . . . _:b418709331 . . . _:b418709330 . _:b418709341 . . . . _:b418709340 . . _:b418709343 . _:b6412169 "While microglia can become activated after exposure to fibrillary A\u03B2 in vitro and are capable of phagocytosing it in vitro [>>28<<-30], it has been reported that in the presence of inflammatory cytokines or certain extracellular matrix proteins, microglia cannot phagocytize A\u03B2 [31]." . _:b6412175 . _:b6412158 . _:b418709342 . . . . _:b418709337 . . . _:b418709336 . _:b418708902 . _:b418709245 . . _:b418709339 . . _:b418708552 . _:b418709338 . . . _:b418709349 . . _:b418708811 . _:b418709348 . _:b418709263 . . _:b418709351 . . . . _:b418709350 . _:b418709165 . _:b418709345 . _:b6412222 "in the rodent midbrain substantia nigra within hours of in vivo administration of two neurotoxins widely used to model parkinsonism in rodents, 6-hydroxydopamine (6-OHDA) [8] and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [>>85<<-87]. Consistent with a role of TNF in contributing to dopaminergic neuron death in chronic parkinsonism, plasma TNF levels were shown to remain elevated in MPTP-treated non-human primates one year after administration of the neurotoxin" . _:b418709344 . _:b418709347 . _:b418709346 . . _:b418708598 . _:b6412187 "Participants in the Baltimore Longitudinal Aging Study also exhibited a reduced risk for AD with the use of NSAIDs, with those patients who had taken NSAIDs for more than 2 years showing the most reduction in AD risk [>>48<<]. Comparison of brains of aged but cognitively normal patients who used NSAIDs chronically with that of cognitively normal patients who did not use NSAIDs revealed no changes in the appearance of senile plaques, but a 3-fold decrease in" . _:b418709357 . _:b418709177 . _:b418709356 . _:b418708609 . _:b418709359 . _:b418709358 . _:b418709353 . _:b418709055 . . _:b418709146 . _:b418709352 . . _:b6412182 . _:b418709355 . . _:b418709354 . . _:b418709365 . _:b418709364 . _:b418709367 . _:b418709366 . _:b6412168 . _:b418709361 . _:b418709310 . _:b418709360 . _:b418709021 . _:b418709363 . _:b418708806 . _:b418709362 . _:b418709373 . _:b418709372 . . _:b418709375 . _:b418709374 . _:b418708736 . _:b418709369 . _:b418708918 . _:b418709368 . _:b418708931 . . _:b418709371 . _:b418708764 . _:b418709370 . . . _:b418709029 . _:b418709381 . . . . _:b418709270 . _:b418709380 . _:b418709034 . _:b418708690 . _:b6412186 "In a study of siblings who all eventually developed AD, regular use of NSAIDs delayed the onset of AD and reduced the risk of AD with each year of use [>>47<<]. Participants in the Baltimore Longitudinal Aging Study also exhibited a reduced risk for AD with the use of NSAIDs, with those patients who had taken NSAIDs for more than 2 years showing the most reduction in AD risk [48]. Comparison of" . _:b418708914 . _:b418709383 . _:b6412153 . _:b418708503 "10"^^ . _:b418708800 . _:b418709382 . _:b418708920 . . _:b418708497 "14"^^ . _:b418708502 "10"^^ . . _:b418709377 . . . _:b418708501 "10"^^ . _:b418709376 . _:b418708786 . _:b418708500 "11"^^ . _:b418709379 . _:b6412233 . _:b418708743 . . _:b418709378 . _:b418708499 "12"^^ . . . _:b418708498 "13"^^ . . . _:b418708510 "7"^^ . _:b6412160 . _:b418708511 "7"^^ . _:b418709384 . . _:b418708763 . _:b418709384 . _:b418708508 "7"^^ . . _:b418708509 "7"^^ . _:b6412174 "effect of A\u03B2 deposition in brain has been recapitulated in aged mice transgenic for a familial AD mutation of APP, in which astrocytes and microglia expressing Il-1\u03B2, IL-6 and TNF have been found surrounding amyloid plaques [>>35<<]. The bacterial endotoxin lipopolysaccharide (LPS), a powerful inducer of inflammatory responses [36], exacerbates the appearance and severity of AD pathology in the APPV717F transgenic mouse [37], the APPswe transgenic mouse [38], and" . . _:b418708782 . . _:b418708506 "8"^^ . _:b418709291 . . _:b418708507 "8"^^ . _:b418709204 . . _:b418709215 . _:b418708504 "8"^^ . _:b418708976 . . _:b418708505 "8"^^ . _:b418708518 "6"^^ . _:b418708756 . _:b6412203 "Immunizing PDAPP mice with A\u03B242 prevented or reduced the progression of AD pathology in these mice, depending on whether the immunization took place before or after the development of plaque pathology [>>64<<]. Vaccination with A\u03B2 peptides also ameliorated cognitive deficits in mice transgenic for a familial AD (FAD) mutation in APP and an FAD mutation in PS1 [65]. As an alternative delivery route, intranasal administration of A\u03B2 peptides" . _:b418708519 "6"^^ . _:b418708516 "6"^^ . _:b418708700 . _:b6412179 . _:b418708517 "6"^^ . . . _:b418708725 . _:b418708514 "6"^^ . . . _:b418708515 "6"^^ . _:b418708970 . _:b418708512 "7"^^ . _:b418708513 "6"^^ . _:b418709122 . _:b418708525 "5"^^ . _:b418708897 . _:b418708524 "5"^^ . _:b6412233 . _:b418708603 . . _:b418708527 "5"^^ . _:b6412255 . . . _:b418708526 "5"^^ . . _:b418708522 "6"^^ . . . _:b6412211 "in AD patients, and the immunizations resulted in significant clearance of A\u03B2 and plaque removal in some of the patients [70,71], as well as a slowing of the cognitive decline in patients who produced antibodies against the peptide [>>72<<]. Unfortunately, the immunization also resulted in dangerous T-lymphocyte meningoencephalitis in some patients, causing the arrest of these trials [70,73]." . . _:b418708523 "6"^^ . . _:b6412180 "Co-addition of TGF-\u03B21, 2 and 3 isoforms with A\u03B2 causes increased A\u03B2 accumulation in organotypic hippocampal slices [>>41<<]. Together, these findings demonstrate the close association between microglia and plaque deposition and the ability of certain chronic inflammatory stimuli to exacerbate and accelerate amyloid-associated pathology. The emerging idea is" . _:b418709273 . _:b418708520 "6"^^ . _:b418708521 "6"^^ . _:b6412157 "evidence of neuroinflammation and cytokine involvement in neurodegenerative diseases" . . . _:b418708714 . . _:b418708533 "5"^^ . _:b418709159 . _:b418708707 . . . _:b418708532 "5"^^ . _:b418708535 "5"^^ . . _:b6412197 . _:b418708534 "5"^^ . _:b418708652 . . _:b418708529 "5"^^ . . . . _:b418708874 . . _:b418708528 "5"^^ . . . _:b418708531 "5"^^ . _:b418708665 . _:b418708530 "5"^^ . . _:b418708541 "5"^^ . . _:b418708540 "5"^^ . . _:b418708543 "5"^^ . _:b418708542 "5"^^ . _:b6412178 "(LPS), a powerful inducer of inflammatory responses [36], exacerbates the appearance and severity of AD pathology in the APPV717F transgenic mouse [37], the APPswe transgenic mouse [38], and the triple-transgenic (3xTgAD) mouse [>>39<<]. In addition, the Transforming Growth Factor-\u03B2 (TGF-\u03B2) cytokine family increases A\u03B2 accumulation in the cerebral blood vessels of mice transgenic for human APP and is upregulated in blood vessels of human patients with Cerebral Amyloid" . . _:b418708537 "5"^^ . . _:b418709003 . . _:b418709239 . _:b418708536 "5"^^ . _:b418709085 . _:b418708539 "5"^^ . _:b6412264 "Consistent with this idea, mSOD1 mice stimulated with LPS secrete more inflammatory mediators, including TNF [135], MCP-1, TGF-\u03B2[>>121<<] and IFN-\u03B3 [136], than control mice." . _:b418708538 "5"^^ . _:b418708937 . . . _:b418708549 "4"^^ . . _:b6412227 "In the first model chronic low dose lipopolysaccharide (LPS) infusion into SNpc of rats results in delayed, selective and progressive loss of nigral DA neurons [>>89<<]. In the second model exposure of pregnant rats to LPS and thus, in utero exposure of embryos to the endotoxin, caused a loss of DA neurons in postnatal brains [90]. Most importantly, chronic infusion of dominant negative TNF inhibitor" . . _:b418708548 "4"^^ . . . _:b418709287 . _:b418708551 "4"^^ . _:b418708649 . _:b418709294 . . . _:b418708550 "4"^^ . . . _:b418708545 "5"^^ . _:b418708544 "5"^^ . _:b6412259 . . _:b6412204 "Vaccination with A\u03B2 peptides also ameliorated cognitive deficits in mice transgenic for a familial AD (FAD) mutation in APP and an FAD mutation in PS1 [>>65<<]. As an alternative delivery route, intranasal administration of A\u03B2 peptides reduced amyloid deposition in AD mouse models [66,67]. A\u03B2 vaccinations were also found successful in reducing A\u03B2 levels in two non-human primates, the rhesus" . _:b418708547 "5"^^ . _:b418709280 . . _:b418708658 . _:b418708546 "5"^^ . _:b6412267 . _:b418708532 . . _:b418708557 "4"^^ . . _:b6412214 . _:b418708556 "4"^^ . . . . _:b418708559 "4"^^ . . _:b418708986 . . _:b418709282 . _:b418708558 "4"^^ . . _:b418708553 "4"^^ . _:b418708841 . . _:b6412271 "For instance, IL-1\u03B2 may not be critical to ALS pathogenesis as genetic deletion of IL-1\u03B2 does not change the lifespan or rate of motor neurodegeneration in mSOD-1 mice [>>142<<]." . _:b418708552 "4"^^ . _:b418708596 . . . _:b418708555 "4"^^ . . _:b418708554 "4"^^ . . . _:b418709250 . _:b418708565 "4"^^ . . . _:b418708564 "4"^^ . _:b6412243 "innate immune response before the onset of clinical symptoms and investigators have been able to discriminate controls from presymptomatic HD mutation carriers by measuring the levels of 3 cytokines, IL-5, IL-6, and IL-10 in plasma [>>113<<]. In brains of mutant htt carriers, microglia are activated before onset of symptoms and increased microglial activation correlates with an increased chance of developing HD symptoms in 5 years [114]." . _:b418708620 . _:b418708567 "4"^^ . _:b418709299 . _:b418708566 "4"^^ . . _:b418708561 "4"^^ . _:b418709355 . _:b418708905 . _:b418708761 . _:b418708748 . _:b418708560 "4"^^ . . _:b6412211 . _:b418708563 "4"^^ . _:b418709284 . _:b418708562 "4"^^ . _:b418708573 "4"^^ . . _:b418708572 "4"^^ . . _:b418708575 "4"^^ . _:b418709143 . _:b418708881 . _:b418709011 . _:b418708574 "4"^^ . _:b418708696 . _:b418709012 . _:b418708569 "4"^^ . _:b6412236 . . _:b418708568 "4"^^ . _:b418708501 . _:b418708571 "4"^^ . . _:b418709057 . _:b418708570 "4"^^ . _:b418709370 . _:b418708836 . _:b418708581 "4"^^ . . . . _:b418709266 . . _:b418708580 "4"^^ . . _:b418708583 "4"^^ . _:b418708769 . . . _:b418708582 "4"^^ . _:b418708577 "4"^^ . _:b418708576 "4"^^ . . _:b418708737 . _:b418708579 "4"^^ . _:b418708578 "4"^^ . _:b418708910 . _:b418708589 "4"^^ . _:b418708812 . _:b418708595 . _:b418708588 "4"^^ . . _:b418708513 . _:b418708591 "4"^^ . . _:b6412220 . _:b418708590 "4"^^ . _:b6412237 . . _:b418708585 "4"^^ . . _:b418708584 "4"^^ . . _:b418709179 . _:b418708587 "4"^^ . _:b418708886 . _:b6412170 "exposure to fibrillary A\u03B2 in vitro and are capable of phagocytosing it in vitro [28-30], it has been reported that in the presence of inflammatory cytokines or certain extracellular matrix proteins, microglia cannot phagocytize A\u03B2 [>>31<<]. This observation has been used to support the idea that the persistence and accumulation of amyloid plaques in vivo may be a direct result of this inhibitory behavior exerted by neuroinflammation." . _:b418708586 "4"^^ . _:b418708597 "4"^^ . _:b418708596 "4"^^ . _:b418708934 . . _:b418708599 "4"^^ . _:b418708571 . _:b418708598 "4"^^ . _:b6412221 "elevated levels of TNF mRNA and protein can be detected in the rodent midbrain substantia nigra within hours of in vivo administration of two neurotoxins widely used to model parkinsonism in rodents, 6-hydroxydopamine (6-OHDA) [>>8<<] and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [85-87]." . . . . _:b418708593 "4"^^ . _:b418709240 . _:b6412158 . _:b418709217 . _:b418708592 "4"^^ . _:b6412237 . _:b418709207 . _:b418708595 "4"^^ . _:b418709116 . _:b418708594 "4"^^ . . . _:b418709098 . _:b418708605 "3"^^ . . _:b418708604 "3"^^ . . . _:b418708648 . _:b418708607 "3"^^ . _:b418708995 . _:b418708919 . _:b418708606 "3"^^ . _:b418708601 "4"^^ . . _:b418709083 . _:b418708846 . _:b418708600 "4"^^ . . _:b6412245 . . _:b418708603 "4"^^ . _:b418708602 "4"^^ . . . _:b418708613 "3"^^ . _:b6412268 . . . _:b418708612 "3"^^ . . _:b418708615 "3"^^ . . _:b418708614 "3"^^ . _:b418709372 . _:b418708609 "3"^^ . _:b418708608 "3"^^ . _:b418708538 . _:b418709138 . _:b418708611 "3"^^ . _:b6412260 . _:b6412194 . _:b418709118 . . _:b418708608 . . _:b418708629 . _:b418708610 "3"^^ . _:b418708621 "3"^^ . _:b418709248 . _:b418708625 . _:b418708620 "3"^^ . _:b418708753 . . _:b418708623 "3"^^ . . _:b418708622 "3"^^ . _:b6412233 . . . . . . _:b418708617 "3"^^ . _:b418708616 "3"^^ . _:b418708997 . "PMC0" . _:b418709226 . . _:b418708619 "3"^^ . _:b418708996 . _:b418708618 "3"^^ . _:b418708999 . . _:b418709374 . _:b418708629 "3"^^ . _:b418708998 . _:b418708628 "3"^^ . _:b418708993 . _:b418708631 "3"^^ . _:b418708992 . _:b418708813 . _:b6412235 . _:b418708630 "3"^^ . _:b418708995 . _:b418708625 "3"^^ . _:b418708994 . _:b418708624 "3"^^ . _:b418709277 . _:b418709005 . . _:b418708627 "3"^^ . _:b418709106 . _:b418709004 . _:b418708626 "3"^^ . _:b418709007 . _:b418708637 "3"^^ . _:b418709006 . _:b6412251 "Interestingly, mutant, but not normal htt activates the IKK complex, the major kinase that leads to phosphorylation-induced degradation of I\u03BABs, leading to increased translocation of NF-\u03BAB dimers to the nucleus in mouse striatal cells [>>120<<]. Since NF-\u03BAB can promote expression of IL-6 and other inflammatory cytokines in glia, such an interaction provides a candidate mechanism by which mutant htt could alter the activity of immune cells leading to an abnormally robust" . _:b418709064 . _:b418708636 "3"^^ . _:b418709001 . _:b418708639 "3"^^ . _:b418709000 . _:b418708638 "3"^^ . _:b418709003 . _:b418708633 "3"^^ . _:b418709002 . . . _:b418709073 . _:b418708632 "3"^^ . _:b418709013 . _:b418708635 "3"^^ . _:b418709012 . . _:b418708634 "3"^^ . _:b418709015 . _:b6412233 . _:b418708645 "3"^^ . _:b418709014 . _:b418708644 "3"^^ . _:b418709009 . . _:b418708647 "3"^^ . _:b418709008 . . _:b6412220 . _:b418708646 "3"^^ . _:b418709011 . _:b418708792 . _:b418708641 "3"^^ . _:b418709010 . _:b418709022 . _:b418708640 "3"^^ . _:b418709021 . _:b6412236 "elevated levels of cytokines acting in an autocrine manner to potentiate inflammatory responses (e.g., auto-amplification of reactive oxygen species, nitric oxide, and superoxide radicals to form highly oxidizing peroxynitrite species)[>>7<<,105-108]. Given that DA neurons in the midbrain have an inherently elevated oxidative intracellular environment as a result of oxidation reactions required for the synthesis of the neurotransmitter dopamine, chronic neuroinflammation is" . _:b418708643 "3"^^ . _:b418709020 . _:b418708642 "3"^^ . _:b418709023 . . _:b418708653 "3"^^ . _:b418709022 . . _:b418708652 "3"^^ . _:b418709017 . . _:b418708655 "3"^^ . _:b418709016 . _:b418708844 . _:b418708654 "3"^^ . _:b418709343 . _:b418709133 . _:b418709019 . _:b418708649 "3"^^ . _:b418709018 . . _:b418708648 "3"^^ . _:b418709029 . . _:b418708557 . _:b418708767 . . . _:b6412235 "idiopathic PD have markedly elevated microglia activation in the pons, basal ganglia, striatum, and frontal and temporal cortical regions irrespective of the number of years with the disease compared to healthy age-matched controls [>>81<<]. Persistent activation of the abundant number of microglia in the midbrain region are likely the direct result of elevated levels of cytokines acting in an autocrine manner to potentiate inflammatory responses (e.g., auto-amplification" . _:b418709028 . . _:b418708651 "3"^^ . . . _:b418708650 "3"^^ . _:b418709031 . . _:b418708661 "3"^^ . _:b418709030 . . _:b418708660 "3"^^ . _:b6412256 "In some ALS disease models the presence of immune cells precedes the disease phenotype [124], and the chemokine MCP-1, a potent chemotactic stimulus for microglia [>>125<<] is elevated in the CSF of ALS patients [126], suggesting that neuroinflammation could contribute to disease progression." . _:b418709341 . _:b418709025 . _:b418708587 . _:b418708663 "3"^^ . _:b418709024 . _:b418708662 "3"^^ . _:b418709027 . . _:b418708657 "3"^^ . _:b418709026 . _:b6412184 "systemic immune responses are present in patients who progress from MCI and go on to develop AD, raising the interesting possibility that this inflammation \"communicome\" may serve as signature for early detection of the disease [>>45<<]." . _:b418708656 "3"^^ . _:b418709037 . . _:b418709223 . _:b418709214 . _:b418708659 "3"^^ . _:b418709036 . _:b418708502 . _:b6412220 "A number of studies have confirmed the presence of inflammatory mediators (including TNF, IL-1\u03B2, IL-6, and IFN\u03B3) in the cerebrospinal fluid (CSF) of patients with PD as well as in the post-mortem SNpc in PD patient brains [>>80<<-84]. Significantly elevated levels of TNF mRNA and protein can be detected in the rodent midbrain substantia nigra within hours of in vivo administration of two neurotoxins widely used to model parkinsonism in rodents, 6-hydroxydopamine" . _:b418708658 "3"^^ . _:b6412148 . _:b418709039 . _:b418708499 . _:b418708840 . _:b418709307 . _:b418708669 "3"^^ . _:b6412149 . _:b418709038 . _:b418709352 . _:b418708668 "3"^^ . _:b6412195 "Peroxisome Proliferator-Activated Receptor-\u03B3 (PPAR\u03B3), a nuclear receptor which is activated by metabolites of prostaglandins generated by the COX enzymes and by certain NSAIDs, is upregulated in concert with the COX enzymes in AD brain [>>42<<]. As such, PPAR\u03B3 activation exerts an anti-inflammatory effect, and PPAR\u03B3 agonists have been shown to inhibit the production of cytokines and pro-inflammatory mediators in response to A\u03B2 [58]." . _:b6412150 . _:b418709033 . _:b418708671 "3"^^ . _:b6412151 . _:b418709032 . . . _:b418709352 . _:b418708719 . _:b418709353 . _:b418708670 "3"^^ . _:b6412200 "Increases in levels of IL-1\u03B2 have been correlated with decreases in LTP in the hippocampus, showing that the cytokine itself may impair memory [>>61<<]. Other evidence, however, suggests that IL-1\u03B2 may not be driving AD pathogenic processes. For example, functional inhibition of IL-1\u03B2 signaling in mice by genetic ablation of the IL1 receptor [62] or by infusion of IL-1ra did not" . _:b418709035 . _:b418709354 . _:b418709355 . _:b418709356 . . _:b418709357 . _:b418708665 "3"^^ . _:b418709034 . _:b418709358 . _:b418709359 . _:b418709344 . _:b6412188 . . _:b418708993 . _:b418708585 . _:b418709345 . _:b418708664 "3"^^ . _:b418709045 . _:b418709346 . _:b418709347 . _:b6412146 . _:b418709348 . _:b418709349 . _:b418708667 "3"^^ . _:b6412147 . _:b418709044 . _:b418709350 . _:b418709351 . _:b418709368 . _:b418709369 . _:b418708666 "3"^^ . _:b6412156 . _:b418709047 . _:b418709370 . _:b418709371 . _:b418709372 . _:b418709373 . . _:b418709046 . _:b418709374 . _:b418708677 "3"^^ . _:b418709375 . _:b418708906 . _:b6412157 . _:b418709360 . _:b418709361 . _:b418708676 "3"^^ . _:b6412158 . _:b418709041 . _:b418709362 . . _:b418709180 . _:b418709363 . _:b418709364 . _:b418709365 . _:b418708679 "3"^^ . _:b6412159 . _:b418709040 . _:b418709366 . _:b418709367 . _:b418709320 . _:b418709321 . _:b418708678 "3"^^ . _:b6412152 . _:b418709043 . _:b418709322 . _:b418709323 . _:b418709324 . _:b418709325 . _:b418708673 "3"^^ . _:b6412153 . _:b418709042 . _:b418708819 . _:b418709326 . _:b418709327 . . _:b418709312 . _:b418709313 . _:b418708672 "3"^^ . _:b418709053 . _:b418709314 . _:b418709315 . _:b6412154 . _:b418709316 . _:b418709317 . _:b418708675 "3"^^ . _:b6412155 . _:b418709052 . _:b418709318 . _:b418709319 . _:b418709336 . _:b418709337 . _:b418708674 "3"^^ . _:b6412164 . _:b418709055 . _:b418709338 . _:b418709339 . _:b418708641 . _:b418709340 . _:b418709341 . _:b418708685 "3"^^ . _:b6412165 . _:b418709054 . _:b418709342 . _:b418709343 . _:b418709328 . _:b418709329 . _:b418708684 "3"^^ . _:b6412166 . _:b418709049 . _:b418709330 . . _:b418709331 . _:b418709339 . _:b418708724 . _:b418709332 . _:b418709333 . . _:b418708687 "3"^^ . _:b6412167 . _:b418709048 . _:b418708952 . _:b418709334 . _:b418709335 . _:b418709288 . _:b418709289 . _:b418708686 "3"^^ . _:b6412160 . _:b418709051 . _:b418709290 . _:b418709291 . _:b418709292 . _:b418708713 . _:b418709293 . _:b418708681 "3"^^ . _:b6412161 . _:b418709050 . _:b418709294 . _:b418709295 . _:b418709280 . _:b418708793 . _:b6412240 "Increases were most pronounced in the caudate putamen where brain pathology is most severe in HD patients [>>111<<]. Increases in labeling of complement proteins in neurons and astrocytes and a 2-5 fold increase in activators and regulators of the classical complement pathway have also been detected in human HD brains by RT-PCR [112]. Lastly, clinical" . _:b418709281 . _:b418708680 "3"^^ . _:b6412162 . _:b418709061 . _:b418709282 . _:b418709283 . . _:b418709284 . _:b418709285 . _:b418708683 "3"^^ . _:b6412163 . _:b418709060 . _:b418709286 . _:b418709287 . _:b418709304 . _:b418709305 . _:b6412240 . _:b418708682 "3"^^ . _:b6412172 . _:b418709063 . _:b418709306 . _:b418709307 . _:b418709243 . _:b418708833 . _:b418709308 . _:b418709309 . _:b418708693 "3"^^ . _:b6412173 . _:b418709062 . _:b418709310 . _:b418709311 . _:b418709296 . _:b418709297 . _:b418708692 "3"^^ . _:b6412174 . _:b418709057 . . _:b418709298 . _:b418709299 . _:b418708808 . _:b418709300 . _:b418709301 . _:b418708695 "3"^^ . _:b6412175 . _:b418709056 . _:b418709302 . _:b418708604 . _:b418709303 . _:b418709256 . . . _:b418709257 . _:b418708694 "3"^^ . _:b6412168 . _:b418709059 . _:b418709258 . . _:b418709259 . _:b418709260 . _:b418708820 . _:b418709261 . _:b418709347 . _:b418708689 "3"^^ . _:b6412169 . _:b418709058 . _:b418709262 . _:b418709263 . _:b418709248 . . . _:b418709249 . . _:b418708688 "3"^^ . _:b6412170 . _:b418709069 . _:b418709250 . _:b418709251 . _:b418709252 . . _:b418709253 . _:b418708691 "3"^^ . _:b6412171 . _:b418709068 . _:b418709254 . _:b418709255 . _:b418709272 . _:b418709273 . . _:b418708690 "3"^^ . _:b6412180 . _:b418709071 . _:b418708894 . _:b418709274 . _:b418709275 . _:b418708779 . _:b418709276 . _:b418709277 . _:b418708701 "3"^^ . _:b6412181 . _:b418709070 . _:b418709278 . _:b418709279 . . _:b418709264 . _:b418709265 . _:b418709048 . _:b418708700 "3"^^ . _:b6412182 . _:b418709065 . _:b418709266 . _:b418709267 . _:b418709268 . . _:b418709269 . _:b418708703 "3"^^ . _:b6412183 . _:b418709064 . _:b418709270 . _:b418709271 . . _:b418708702 "3"^^ . _:b6412176 . _:b418709067 . _:b6412205 "As an alternative delivery route, intranasal administration of A\u03B2 peptides reduced amyloid deposition in AD mouse models [>>66<<,67]. A\u03B2 vaccinations were also found successful in reducing A\u03B2 levels in two non-human primates, the rhesus monkey [68] and the Caribbean vervet [69]. A clinical trial of A\u03B242 vaccinations was undertaken by Elan Pharmaceuticals in AD" . . _:b6412220 . _:b6412187 . _:b418708697 "3"^^ . _:b6412177 . _:b418709066 . _:b418708696 "3"^^ . _:b6412178 . _:b418709077 . _:b418708699 "3"^^ . _:b6412179 . _:b418709076 . _:b418708698 "3"^^ . _:b6412188 . _:b418709079 . _:b418708790 . _:b418708798 . _:b418708709 "3"^^ . _:b6412189 . _:b418709309 . _:b418709078 . . _:b418709323 . _:b418708708 "3"^^ . _:b6412190 . _:b418709073 . _:b418708635 . _:b418708950 . _:b418708711 "3"^^ . _:b6412191 . _:b418709072 . . _:b418709367 . _:b418708710 "3"^^ . _:b6412184 . _:b418709075 . . _:b418708543 . _:b6412185 . _:b418709074 . _:b418708705 "3"^^ . _:b418708704 "3"^^ . _:b6412186 . _:b418709085 . . _:b418708707 "3"^^ . _:b6412187 . _:b418709084 . _:b6412263 . _:b418709175 . _:b418708706 "3"^^ . _:b6412196 . _:b418709087 . . _:b418709168 . . . _:b418708717 "3"^^ . _:b6412197 . _:b418709086 . _:b418708732 . _:b418708716 "3"^^ . _:b6412198 . _:b418709081 . _:b418708981 . . _:b6412256 . _:b418709200 . . _:b418708719 "3"^^ . _:b6412199 . _:b418709080 . _:b418708718 "3"^^ . _:b6412192 . _:b418709083 . _:b418708713 "3"^^ . _:b6412193 . _:b418709082 . . _:b418708774 . _:b418708712 "3"^^ . _:b6412194 . _:b418709093 . _:b6412218 "In short, A\u03B2 immunotherapy holds promise but will need to be made safer and more effective in its ability to generate good antibody titers in the elderly [>>78<<]. If these novel immunogens can enhance A\u03B2 antibody generation without the adverse events seen in the earlier clinical trial, neuroimmune modulation by vaccination may become an effective way to prevent AD." . _:b418708715 "3"^^ . _:b6412195 . _:b418709092 . . _:b418708714 "3"^^ . _:b6412204 . _:b418709095 . . . _:b6412190 . _:b418708725 "3"^^ . _:b6412205 . _:b418709094 . _:b418708724 "3"^^ . _:b6412206 . _:b418709342 . _:b418709089 . . _:b418708727 "3"^^ . _:b6412207 . _:b418709088 . _:b418709384 . _:b418709128 . _:b418708726 "3"^^ . _:b6412200 . _:b418709091 . _:b418708721 "3"^^ . _:b6412201 . _:b418709090 . _:b418709376 . _:b418709377 . _:b418708720 "3"^^ . _:b6412202 . _:b418709101 . _:b418709378 . . _:b418709379 . _:b418709380 . _:b418709381 . _:b6412167 "In addition to producing cytokines and other pro-inflammatory mediators [19,>>26<<], microglia have also been reported to exert toxicity on neurons that have been pre-exposed to low concentrations of A\u03B242 via a CD14-dependent process [27]." . _:b418708991 . _:b418708723 "3"^^ . _:b6412203 . _:b418709100 . _:b418709382 . _:b418709383 . _:b418709369 . _:b418708722 "3"^^ . _:b6412212 . _:b418709103 . . _:b418708733 "3"^^ . _:b6412213 . _:b418709102 . _:b418708732 "3"^^ . _:b6412214 . _:b418709097 . _:b418708949 . _:b418708735 "3"^^ . _:b6412215 . _:b418709096 . _:b418709096 . _:b418709097 . _:b6412164 "Human microglia display an activated phenotype when they surround plaques [>>23<<] that includes upregulation of Human Leukocyte Antigen-DR (HLA-DR) [18]." . _:b418708734 "3"^^ . _:b6412208 . _:b418709099 . _:b418709098 . _:b418709099 . _:b418709100 . _:b418709101 . _:b418708729 "3"^^ . _:b6412209 . _:b418709098 . _:b418709102 . _:b418709103 . . _:b418709088 . _:b418709089 . _:b6412222 . _:b418708728 "3"^^ . _:b6412210 . _:b418709109 . _:b418709090 . _:b418709091 . _:b418709092 . _:b418709093 . _:b418708731 "3"^^ . _:b6412211 . _:b418709108 . _:b418709094 . _:b418709095 . _:b6412169 . _:b418709112 . _:b418709113 . _:b418708730 "3"^^ . _:b6412220 . _:b418709111 . _:b418709114 . _:b418709115 . _:b6412168 "In addition to producing cytokines and other pro-inflammatory mediators [19,26], microglia have also been reported to exert toxicity on neurons that have been pre-exposed to low concentrations of A\u03B242 via a CD14-dependent process [>>27<<]. Although it is clear that not all microglia activation is injurious to neurons, it is becoming widely accepted that a type of neurotoxic microglia phenotype has a central role in the pathophysiology of AD." . . _:b418709116 . _:b418708741 "2"^^ . _:b418709117 . _:b418709118 . _:b6412221 . _:b418709110 . . _:b418709119 . _:b418709020 . _:b418709104 . _:b418708740 "2"^^ . _:b418709105 . _:b418709106 . _:b6412222 . _:b418709105 . _:b418709107 . . . _:b418709108 . _:b418708743 "2"^^ . _:b6412173 . _:b418709109 . _:b418709110 . _:b6412223 . _:b418709104 . . _:b418709111 . _:b418709064 . _:b418708742 "2"^^ . _:b418709193 . _:b418709065 . _:b418709066 . _:b6412216 . _:b418709107 . _:b418708542 . _:b418709067 . _:b418709068 . _:b418709069 . _:b418708737 "3"^^ . _:b6412217 . _:b418709106 . _:b418709070 . _:b418709071 . _:b418708582 . _:b418709056 . _:b418709057 . _:b418708736 "3"^^ . _:b6412218 . _:b418709117 . _:b418709058 . _:b418709059 . _:b418708701 . _:b418709060 . _:b418709061 . _:b418708739 "3"^^ . _:b6412219 . _:b418709116 . _:b418709062 . _:b418709063 . _:b418709080 . . _:b418709081 . _:b418708738 "3"^^ . _:b6412228 . _:b418709119 . _:b418709082 . _:b418709083 . _:b418709084 . _:b418708749 "2"^^ . _:b418709085 . _:b418709086 . _:b6412229 . _:b418709118 . _:b418709087 . . _:b418709072 . _:b418708748 "2"^^ . _:b418709073 . . _:b418709074 . _:b6412230 . _:b418709113 . . _:b418709075 . _:b418709076 . _:b418708751 "2"^^ . _:b418709077 . _:b418709078 . _:b6412231 . _:b418709112 . _:b418709079 . . _:b418709032 . _:b418708750 "2"^^ . _:b418709033 . _:b418709034 . _:b6412224 . _:b418709115 . . _:b418709035 . _:b418709036 . _:b418708745 "2"^^ . _:b418709037 . _:b418709038 . _:b6412225 . _:b418709114 . _:b418709039 . _:b418709135 . . _:b418709024 . _:b418708744 "2"^^ . _:b418709025 . _:b418709026 . _:b6412226 . _:b418709125 . _:b418708614 . _:b418709027 . _:b418709028 . _:b418708747 "2"^^ . _:b418709029 . _:b418709030 . _:b6412227 . _:b418709124 . _:b418709031 . _:b6412204 . _:b418708505 . _:b418709048 . . _:b418709049 . _:b418708746 "2"^^ . _:b418709050 . _:b6412236 . _:b418709353 . _:b418709127 . _:b418709051 . _:b6412178 . _:b418709052 . _:b418708873 . _:b418708757 "2"^^ . _:b418709053 . _:b418709054 . _:b6412237 . _:b418709126 . . . _:b418709055 . _:b418709040 . _:b418708756 "2"^^ . _:b418709041 . _:b418709042 . _:b6412238 . _:b418709121 . _:b418709043 . _:b418709044 . . _:b418708759 "2"^^ . _:b418709045 . _:b418709046 . _:b6412239 . _:b418709120 . _:b418709047 . _:b6412234 . _:b418709000 . _:b418708758 "2"^^ . _:b418709001 . _:b418709002 . _:b6412232 . _:b418709123 . _:b418709003 . _:b418709004 . _:b418708753 "2"^^ . _:b418709005 . _:b418709006 . _:b6412233 . _:b418709253 . _:b418709122 . _:b418709007 . _:b418708992 . _:b418708752 "2"^^ . _:b418708993 . . _:b418708994 . _:b6412234 . _:b418709133 . _:b418708531 . _:b418708995 . _:b418708996 . _:b418708755 "2"^^ . _:b418708997 . _:b418708998 . _:b6412235 . _:b418709132 . _:b418709093 . _:b418708999 . . _:b418708962 . . _:b418709016 . . _:b418708510 . _:b418708754 "2"^^ . _:b418708912 . . _:b418709017 . _:b418709018 . _:b6412244 . _:b418709135 . _:b418709019 . _:b418709020 . _:b418708765 "2"^^ . _:b418708853 . _:b418709021 . _:b418709022 . _:b6412245 . _:b418709134 . _:b418709023 . _:b418709008 . _:b6412183 . _:b418708764 "2"^^ . _:b418709009 . . _:b6412246 . _:b418709139 . _:b418709129 . _:b418708655 . _:b418709010 . _:b418709011 . _:b418708518 . _:b418709012 . . _:b418708573 . _:b418709013 . _:b418708767 "2"^^ . _:b418709014 . _:b6412247 . _:b418709128 . _:b418709015 . . _:b418709224 . . _:b418708766 "2"^^ . _:b418709225 . . _:b6412240 . _:b418709131 . _:b418709226 . _:b418709227 . _:b418709228 . _:b418708933 . _:b418708761 "2"^^ . _:b418708954 . _:b418709229 . _:b418709230 . _:b6412241 . _:b418709130 . _:b418709231 . _:b6412153 "Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines [>>5<<-8]. Neuropathological and neuroradiological studies indicate that neuroinflammatory responses may begin prior to significant loss of neuronal populations in the progression of these diseases." . _:b418709216 . . _:b418709217 . _:b418708760 "2"^^ . . _:b418709218 . _:b6412242 . _:b418709141 . . _:b418709018 . _:b418709219 . _:b418709220 . _:b418708763 "2"^^ . _:b418709363 . _:b418709221 . _:b418709222 . _:b6412243 . _:b418709152 . _:b418709140 . _:b418709223 . _:b418709240 . _:b418708762 "2"^^ . _:b418709241 . _:b418709242 . _:b6412252 . _:b418709143 . _:b418709243 . . _:b418709244 . _:b418708512 . . _:b418709306 . _:b418709031 . _:b418709245 . _:b418708773 "2"^^ . _:b418709246 . _:b6412253 . _:b418709142 . . _:b6412166 "In addition to producing cytokines and other pro-inflammatory mediators [>>19<<,26], microglia have also been reported to exert toxicity on neurons that have been pre-exposed to low concentrations of A\u03B242 via a CD14-dependent process [27]." . _:b418709247 . . _:b418709232 . _:b418708772 "2"^^ . . _:b418709233 . _:b418709234 . _:b6412254 . _:b418709137 . _:b418709235 . . _:b418709236 . _:b418708775 "2"^^ . _:b418709237 . . _:b6412255 . _:b418709136 . _:b418709238 . _:b418709239 . _:b418709192 . _:b418708774 "2"^^ . _:b418709193 . . _:b6412248 . _:b418709139 . _:b418709194 . _:b418709195 . _:b418709196 . _:b418708769 "2"^^ . _:b418709197 . _:b418709198 . _:b6412249 . _:b418709138 . . _:b418709199 . _:b418709184 . _:b418708768 "2"^^ . _:b6412194 "For example, the activation of complement factor C3, the central component of the complement system and a key inflammatory protein may be necessary for plaque clearance by microglia in the AD-afflicted brain [56,>>57<<]. In addition, an important component of any inflammatory response is the activation of anti-inflammatory loops that serve to limit and resolve the initial inflammatory response. The Peroxisome Proliferator-Activated Receptor-\u03B3 (PPAR\u03B3), a" . _:b418709185 . _:b418709186 . _:b6412250 . _:b418709149 . _:b418709187 . _:b418709188 . . _:b418709189 . _:b418708771 "2"^^ . _:b418709190 . _:b6412251 . _:b418709148 . _:b418709191 . _:b418709208 . . _:b418709209 . _:b418708770 "2"^^ . . _:b6412260 . _:b6412208 . _:b418709151 . _:b418708913 . _:b418709210 . . _:b418709211 . _:b418709212 . _:b418708781 "2"^^ . _:b418709213 . _:b418709214 . _:b6412261 . _:b418709150 . _:b418709215 . _:b418708943 . . _:b418709200 . _:b418709373 . _:b418708780 "2"^^ . _:b418709297 . _:b418709201 . . _:b6412262 . _:b418709145 . _:b418709202 . _:b418709203 . _:b418709082 . . _:b418709204 . _:b418708783 "2"^^ . _:b418709205 . _:b418709206 . _:b6412263 . _:b418709144 . . _:b418709207 . _:b418709160 . _:b6412152 "Owing to the chronic and sustained nature of the inflammation, there is often compromise of the BBB which increases infiltration of peripheral macrophages into the brain parenchyma to further perpetuate the inflammation [>>1<<]. Rather than serving a protective role as does acute neuroinflammation, chronic neuroinflammation is most often detrimental and damaging to nervous tissue. Thus, whether neuroinflammation has beneficial or harmful outcomes in the brain" . _:b418708782 "2"^^ . _:b418709161 . _:b418709162 . _:b6412256 . _:b418709147 . _:b418709163 . _:b418709164 . _:b418708777 "2"^^ . _:b418709249 . _:b418709165 . _:b418709166 . _:b6412257 . _:b418709146 . _:b418709167 . _:b418709152 . _:b418708776 "2"^^ . . _:b418709153 . _:b418709154 . _:b6412258 . _:b418709157 . _:b418709155 . _:b418708647 . _:b418709156 . . _:b418708779 "2"^^ . _:b418709157 . _:b418709158 . _:b6412259 . _:b418709156 . _:b418709159 . _:b418709176 . _:b418708778 "2"^^ . _:b418709177 . . _:b6412268 . _:b418709159 . _:b418709178 . . _:b418709179 . _:b418709180 . _:b418708789 "2"^^ . _:b418709181 . _:b418709182 . _:b6412269 . _:b418709158 . . _:b418709183 . _:b418709168 . _:b418708788 "2"^^ . _:b6412220 . _:b418709169 . . _:b418709170 . _:b6412270 . _:b418709153 . _:b418709171 . _:b418709172 . _:b418708791 "2"^^ . _:b418709173 . . _:b6412271 . _:b418709152 . _:b418709174 . _:b418709175 . _:b6412158 . _:b418708541 . _:b418709128 . _:b418708790 "2"^^ . _:b418709129 . _:b418709130 . _:b6412264 . _:b418709155 . _:b418709131 . _:b418708642 . _:b418709132 . _:b418708785 "2"^^ . _:b418709290 . _:b418709133 . _:b418709134 . _:b6412265 . _:b418709154 . _:b418709135 . _:b6412173 "but not diffuse in human AD patients, and in mice transgenic for mutant APP [33], it has been postulated that microglia play a role in the conversion of diffuse to neuritic senile plaques but not in the origin of diffuse plaques [>>34<<]. Specifically, post-mortem analyses of microglia density in the neocortex of three groups of nondemented individuals at different stages of senile plaque formation versus AD patients revealed that the mean density of microglia was" . _:b418709145 . _:b418709120 . _:b418708784 "2"^^ . . _:b418709121 . _:b418709122 . _:b6412266 . _:b418709165 . _:b418708903 . _:b418709123 . _:b418709124 . _:b6412201 "For example, functional inhibition of IL-1\u03B2 signaling in mice by genetic ablation of the IL1 receptor [>>62<<] or by infusion of IL-1ra did not modulate A\u03B2 deposition." . . _:b418708787 "2"^^ . _:b418709125 . _:b418709126 . _:b6412267 . _:b418709164 . _:b418709127 . _:b418709144 . _:b418708786 "2"^^ . _:b418709145 . . _:b418709167 . _:b418709146 . _:b418709147 . _:b418709148 . _:b418708797 "2"^^ . _:b418709149 . _:b418709150 . _:b418709166 . _:b418709151 . _:b418709136 . _:b418708796 "2"^^ . _:b418709137 . _:b418709138 . _:b418709161 . _:b418709139 . _:b418709140 . _:b418708799 "2"^^ . _:b418709141 . . _:b418709142 . _:b418709160 . _:b418709143 . _:b418708840 . _:b418709099 . _:b418708798 "2"^^ . _:b418708841 . _:b418708842 . _:b418709163 . _:b418708955 . . _:b418708843 . _:b418708844 . _:b418708793 "2"^^ . _:b418708845 . _:b418708846 . _:b418709162 . _:b418708847 . _:b418708832 . _:b418708792 "2"^^ . _:b418708833 . . _:b418709173 . _:b418708834 . . _:b418708835 . . _:b418709340 . _:b418708836 . _:b418708795 "2"^^ . _:b418709262 . _:b418708837 . _:b418708838 . _:b418709172 . _:b418708839 . _:b418708856 . _:b418708794 "2"^^ . _:b418709178 . _:b418708857 . _:b418708858 . _:b418709175 . . _:b418708859 . _:b418709258 . _:b418708860 . _:b418708861 . _:b418708805 "2"^^ . _:b418708680 . _:b418708862 . _:b418709174 . _:b418708863 . _:b418708848 . _:b418708849 . _:b6412226 . _:b418708804 "2"^^ . _:b418708850 . _:b418709169 . _:b418708851 . _:b418708852 . _:b418708853 . _:b418708807 "2"^^ . _:b418708854 . _:b418709168 . _:b418708854 . _:b418708855 . _:b418708808 . _:b6412253 . _:b418708809 . _:b418708806 "2"^^ . _:b418708810 . _:b418709171 . _:b418708811 . . _:b418708812 . _:b418708801 "2"^^ . _:b418708813 . _:b418708814 . _:b418709170 . _:b418708563 . _:b418708815 . _:b418708800 . . _:b418708801 . _:b418708800 "2"^^ . . _:b418708802 . _:b418709181 . . _:b418708803 . _:b418708804 . . _:b418708805 . _:b418708803 "2"^^ . _:b418708806 . _:b418709265 . _:b418709180 . _:b418708807 . _:b418708824 . . _:b418708802 "2"^^ . _:b418708825 . _:b418708634 . _:b418709183 . _:b418708826 . _:b418708640 . _:b418708827 . _:b418708828 . _:b418709232 . _:b418708829 . _:b418708813 "2"^^ . _:b418708830 . _:b418709182 . _:b418708831 . _:b418708816 . _:b418708817 . _:b418708812 "2"^^ . _:b418708818 . _:b418709177 . _:b418708819 . _:b418708820 . _:b418708858 . _:b418708821 . _:b418708815 "2"^^ . _:b418708822 . _:b418709176 . _:b418708823 . _:b418708776 . _:b6412232 . _:b418709120 . _:b418708777 . _:b418708814 "2"^^ . _:b418708778 . _:b6412159 "Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [>>18<<] and since then, the association between neuroinflammation and AD has been extensively investigated [7,19-24] and reviewed [19,25]." . _:b418709179 . _:b418708779 . _:b418708566 . _:b418708780 . _:b418708537 . _:b418708809 "2"^^ . _:b418708781 . . _:b418709178 . _:b418708782 . _:b418708783 . . _:b418708768 . _:b418708769 . _:b418708808 "2"^^ . _:b418708770 . _:b418709189 . _:b418708564 . _:b418709086 . _:b418708771 . . _:b418708772 . _:b418708773 . _:b418708811 "2"^^ . _:b418708654 . _:b418708774 . _:b418709188 . _:b418708775 . _:b418708792 . _:b418708863 . _:b418708793 . _:b418708810 "2"^^ . _:b418708794 . _:b418709191 . _:b418708795 . . _:b418708796 . . _:b418708821 "2"^^ . _:b418708797 . _:b418708798 . _:b418709190 . . _:b418708799 . _:b418708784 . _:b418708785 . _:b418708820 "2"^^ . _:b418708786 . _:b418709185 . _:b418708787 . _:b418708788 . _:b418708789 . _:b418708823 "2"^^ . _:b418708790 . _:b418709184 . _:b418708791 . _:b418708549 . _:b418708814 . _:b418708744 . . _:b418708754 . _:b418708822 "2"^^ . _:b418708745 . _:b418708746 . _:b418709187 . . _:b418708747 . _:b418708748 . _:b418708749 . _:b418708817 "2"^^ . _:b418708802 . _:b418709186 . _:b418708750 . . . _:b418708964 . _:b418708751 . _:b418708736 . _:b418708737 . _:b418708899 . _:b418708816 "2"^^ . . _:b418709197 . _:b418708738 . _:b418708739 . _:b418708740 . _:b418708741 . _:b418708819 "2"^^ . _:b418708742 . _:b418709224 . _:b418709196 . _:b418708743 . _:b418708760 . . _:b418708818 "2"^^ . _:b418708761 . _:b418708762 . _:b418709199 . _:b418708763 . _:b418708764 . . _:b418708829 "2"^^ . _:b418708765 . _:b418708766 . _:b418709198 . _:b418708767 . _:b418708752 . _:b418708753 . _:b418708828 "2"^^ . _:b418708754 . _:b418709193 . _:b418708755 . _:b418708756 . _:b418708757 . _:b418708831 "2"^^ . _:b418708758 . _:b418709192 . _:b418708759 . _:b418708968 . . _:b418708830 "2"^^ . _:b418708969 . _:b418708970 . _:b418709195 . _:b418708971 . _:b418708972 . . _:b418708825 "2"^^ . _:b418708973 . _:b418708974 . _:b418709194 . _:b418708583 . _:b418708975 . _:b418708960 . _:b418708961 . _:b418708824 "2"^^ . _:b418708962 . _:b418709205 . _:b418708963 . _:b418708964 . _:b418708965 . _:b418708827 "2"^^ . _:b418708966 . _:b418709204 . _:b418708967 . _:b418708984 . _:b418708985 . _:b418708826 "2"^^ . _:b418708986 . _:b6412210 "A clinical trial of A\u03B242 vaccinations was undertaken by Elan Pharmaceuticals in AD patients, and the immunizations resulted in significant clearance of A\u03B2 and plaque removal in some of the patients [70,>>71<<], as well as a slowing of the cognitive decline in patients who produced antibodies against the peptide [72]." . _:b418709207 . _:b418708963 . _:b418708987 . _:b418708988 . _:b418708989 . _:b418708837 "2"^^ . _:b418708990 . _:b418709206 . _:b418709119 . _:b418708991 . . _:b418708976 . _:b418708977 . _:b418708836 "2"^^ . _:b418708978 . _:b418709201 . _:b418708979 . _:b418708980 . _:b418708981 . _:b418709357 . _:b418708839 "2"^^ . _:b418708982 . _:b418709200 . . _:b418708983 . . _:b418709205 . . _:b418708936 . _:b418708937 . _:b418708838 "2"^^ . . _:b418709203 . _:b418708938 . _:b418708939 . _:b418708940 . _:b418708941 . _:b418708833 "2"^^ . . _:b418709202 . _:b418708942 . _:b418708943 . _:b418708928 . _:b418708929 . _:b418708832 "2"^^ . _:b418708930 . _:b418709213 . _:b418708931 . _:b418708932 . . _:b418708835 "2"^^ . _:b418708933 . . _:b418709212 . _:b418708934 . _:b418708935 . _:b418708952 . _:b418708953 . _:b418708834 "2"^^ . _:b418708954 . _:b418709215 . _:b418708955 . _:b418708956 . _:b418708957 . _:b418708845 "2"^^ . _:b418708958 . _:b418709214 . _:b418708959 . _:b418708944 . _:b6412189 . _:b418708945 . _:b418708844 "2"^^ . _:b418708946 . _:b418709209 . _:b418708947 . . _:b418708948 . _:b418708949 . _:b6412249 . _:b418708847 "2"^^ . _:b418708950 . _:b418709212 . _:b418709208 . _:b418708951 . . _:b418708904 . _:b418708905 . _:b418708846 "2"^^ . . _:b418709211 . _:b418708906 . _:b418708907 . _:b418708908 . _:b418708909 . _:b418708841 "2"^^ . _:b418708910 . _:b418709210 . . . _:b6412227 . _:b418708911 . _:b418708896 . _:b418708897 . _:b418708840 "2"^^ . _:b418708898 . _:b418709221 . _:b418708899 . _:b418708900 . . _:b418708843 "2"^^ . _:b418708901 . _:b418708902 . _:b418709220 . _:b418708903 . _:b418708920 . _:b418708921 . _:b418708842 "2"^^ . _:b418708922 . _:b6412206 "As an alternative delivery route, intranasal administration of A\u03B2 peptides reduced amyloid deposition in AD mouse models [66,>>67<<]. A\u03B2 vaccinations were also found successful in reducing A\u03B2 levels in two non-human primates, the rhesus monkey [68] and the Caribbean vervet [69]. A clinical trial of A\u03B242 vaccinations was undertaken by Elan Pharmaceuticals in AD" . _:b418709223 . _:b418708687 . _:b418708923 . _:b418708924 . _:b6412266 . _:b418708925 . _:b6412243 . _:b418708853 "2"^^ . _:b418708926 . _:b6412250 . _:b418709222 . _:b418708927 . _:b6412158 . _:b418708657 . _:b418708912 . _:b418708913 . _:b6412242 . _:b418708852 "2"^^ . _:b418708914 . _:b418709217 . _:b418709062 . _:b418708865 . _:b418708915 . _:b418708916 . _:b418708917 . _:b418708855 "2"^^ . _:b418708918 . _:b418709216 . _:b418708919 . _:b6412205 . _:b418708876 . _:b418708872 . _:b6412146 _:b6412152 . _:b418708854 "2"^^ . _:b418708873 . _:b6412146 _:b6412153 . _:b418709219 . _:b418708874 . _:b418708875 . . _:b418708876 . _:b6412146 _:b6412148 . _:b418708849 "2"^^ . _:b418708877 . _:b6412146 _:b6412149 . _:b418709218 . _:b418708878 . _:b6412146 _:b6412150 . _:b418708879 . _:b418708621 . _:b418708864 . _:b6412146 _:b6412151 . _:b418708865 . _:b418709259 . _:b418708848 "2"^^ . _:b418708866 . _:b418709229 . _:b418708867 . . _:b418708868 . _:b6412146 _:b6412147 . . _:b418708851 "2"^^ . _:b418708869 . _:b418708870 . _:b418709228 . . . _:b418708830 . _:b418708871 . . _:b418708888 . . _:b418708889 . _:b418708850 "2"^^ . _:b418708890 . _:b418709231 . _:b418708891 . _:b6412244 . _:b418708892 . _:b418708893 . _:b418708861 "2"^^ . _:b418708894 . _:b418709230 . _:b418708895 . _:b418708880 . _:b418708881 . _:b418708860 "2"^^ . . _:b418709225 . _:b418708882 . . _:b6412177 "The bacterial endotoxin lipopolysaccharide (LPS), a powerful inducer of inflammatory responses [36], exacerbates the appearance and severity of AD pathology in the APPV717F transgenic mouse [37], the APPswe transgenic mouse [>>38<<], and the triple-transgenic (3xTgAD) mouse [39]." . _:b418708883 . _:b6412157 _:b6412158 . _:b6412157 _:b6412159 . _:b418708884 . _:b6412154 _:b6412156 . _:b418708863 "2"^^ . _:b418708885 . _:b418708527 . _:b418709224 . _:b418708886 . _:b418708887 . _:b6412199 . _:b418708584 . . _:b418708585 . _:b418708862 "2"^^ . _:b418708586 . _:b418709227 . _:b418708587 . _:b6412154 _:b6412155 . _:b418708588 . _:b418708589 . _:b418709065 . _:b418708857 "2"^^ . _:b418708590 . _:b418709226 . _:b418708591 . _:b418708576 . _:b418708577 . _:b418708856 "2"^^ . _:b418708730 . _:b418709237 . _:b418708578 . _:b418708579 . _:b418708580 . _:b6412157 _:b6412176 . _:b6412181 "Cyclooxygenase 2 (COX2), a pro-inflammatory protein that is one of the targets of non-steroidal anti-inflammatory drugs (NSAIDs), and its homolog COX-1 [>>42<<], are elevated in AD brains [43]." . _:b418708859 "2"^^ . _:b418708581 . _:b6412157 _:b6412177 . _:b418709236 . _:b418708582 . . _:b418708583 . _:b6412157 _:b6412178 . _:b6412157 _:b6412179 . _:b418708600 . _:b6412157 _:b6412180 . _:b418708858 "2"^^ . _:b418708601 . _:b6412157 _:b6412181 . _:b418709239 . _:b418708602 . _:b6412157 _:b6412182 . _:b418708603 . _:b6412157 _:b6412183 . _:b418708604 . _:b6412157 _:b6412184 . _:b418708869 "2"^^ . _:b418708605 . _:b6412157 _:b6412185 . _:b418709238 . _:b418709100 . _:b418708606 . . _:b418708607 . _:b6412157 _:b6412186 . _:b6412157 _:b6412187 . _:b418708592 . _:b6412157 _:b6412188 . _:b6412251 . _:b418708868 "2"^^ . _:b418708593 . _:b6412157 _:b6412189 . _:b418709233 . . _:b418708594 . _:b6412157 _:b6412190 . _:b418708595 . _:b6412157 _:b6412191 . _:b418708898 . _:b418708596 . . _:b418708871 "2"^^ . _:b418708597 . _:b6412157 _:b6412160 . _:b6412157 _:b6412161 . _:b418709232 . _:b418708598 . _:b6412157 _:b6412162 . _:b418708599 . _:b6412157 _:b6412163 . _:b418708552 . . _:b418708870 "2"^^ . _:b418708553 . _:b6412157 _:b6412164 . _:b6412157 _:b6412165 . _:b418709235 . _:b418708554 . _:b6412157 _:b6412166 . _:b418708555 . _:b6412157 _:b6412167 . _:b418708556 . . _:b418709292 . _:b418708865 "2"^^ . _:b418708557 . _:b6412157 _:b6412168 . _:b6412157 _:b6412169 . _:b418709234 . _:b418708558 . _:b6412157 _:b6412170 . _:b418708559 . _:b6412157 _:b6412171 . _:b418708544 . _:b6412157 _:b6412172 . _:b418708864 "2"^^ . _:b418708545 . _:b6412157 _:b6412173 . _:b418709245 . _:b418708546 . . _:b418709046 . _:b418708547 . _:b6412157 _:b6412174 . _:b6412157 _:b6412175 . _:b418708548 . _:b6412157 _:b6412208 . _:b418708867 "2"^^ . _:b418708549 . _:b6412157 _:b6412209 . _:b418709244 . _:b418708550 . _:b6412157 _:b6412210 . _:b418708551 . _:b6412157 _:b6412211 . _:b418708568 . . . _:b418708866 "2"^^ . _:b418708569 . _:b6412157 _:b6412212 . . . _:b418709247 . _:b418708570 . _:b6412157 _:b6412213 . _:b6412157 _:b6412214 . _:b418708571 . . _:b418708572 . _:b6412157 _:b6412215 . . _:b418708877 "2"^^ . _:b418708573 . _:b6412157 _:b6412216 . _:b6412157 _:b6412217 . _:b418709246 . _:b418708574 . _:b6412157 _:b6412218 . _:b418708575 . _:b6412157 _:b6412219 . _:b418708560 . _:b6412157 _:b6412220 . _:b418708876 "2"^^ . _:b418708561 . _:b6412157 _:b6412221 . _:b418709241 . _:b418709154 . _:b418708562 . _:b6412157 _:b6412222 . _:b418708563 . _:b6412157 _:b6412223 . _:b418708809 . _:b418708564 . _:b6412157 _:b6412192 . _:b418708879 "2"^^ . _:b418708565 . _:b6412157 _:b6412193 . _:b418709240 . _:b418708566 . . _:b418708567 . _:b6412157 _:b6412194 . _:b6412157 _:b6412195 . _:b418708520 . _:b6412157 _:b6412196 . _:b418708878 "2"^^ . . _:b418708521 . _:b6412157 _:b6412197 . _:b418709243 . _:b418708522 . _:b6412157 _:b6412198 . _:b418709366 . _:b418708523 . _:b6412157 _:b6412199 . _:b418708524 . _:b6412157 _:b6412200 . _:b418708873 "2"^^ . . _:b418708525 . _:b6412157 _:b6412201 . _:b418709242 . _:b418708526 . _:b6412157 _:b6412202 . _:b418709142 . _:b418708527 . _:b6412157 _:b6412203 . _:b418709336 . _:b418708512 . _:b6412157 _:b6412204 . _:b418708872 "2"^^ . _:b418708513 . _:b418708741 . _:b418708514 . _:b6412157 _:b6412205 . . _:b418708515 . _:b6412157 _:b6412206 . _:b6412157 _:b6412207 . . _:b418708516 . _:b6412157 _:b6412240 . _:b418708875 "2"^^ . _:b418708517 . _:b418708740 . _:b418709264 . _:b418708518 . _:b6412157 _:b6412241 . _:b6412157 _:b6412242 . _:b418708519 . _:b6412157 _:b6412243 . _:b418708536 . _:b6412157 _:b6412244 . _:b418708997 . _:b418708874 "2"^^ . _:b418708537 . _:b418708743 . _:b418708538 . _:b6412157 _:b6412245 . _:b6412157 _:b6412246 . _:b418708539 . _:b6412157 _:b6412247 . _:b418708540 . _:b6412157 _:b6412248 . _:b418708885 "2"^^ . _:b418708541 . _:b418708742 . _:b418708992 . _:b418708542 . _:b6412157 _:b6412249 . _:b6412157 _:b6412250 . _:b418708543 . . . _:b418708528 . _:b6412157 _:b6412251 . _:b6412157 _:b6412252 . _:b418708884 "2"^^ . _:b418708600 . _:b418708529 . _:b418708737 . _:b418709303 . _:b418708530 . _:b6412157 _:b6412253 . _:b6412157 _:b6412254 . _:b418708531 . _:b6412157 _:b6412255 . _:b418708532 . _:b6412157 _:b6412224 . _:b418708887 "2"^^ . _:b418708533 . _:b418708736 . _:b418708534 . _:b6412157 _:b6412225 . _:b6412157 _:b6412226 . _:b418708535 . _:b6412157 _:b6412227 . _:b418708797 . _:b418708886 "2"^^ . _:b6412157 _:b6412228 . _:b418708739 . _:b6412157 _:b6412229 . _:b6412157 _:b6412230 . _:b6412157 _:b6412231 . _:b6412157 _:b6412232 . _:b6412238 "Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that has been linked to mutations in the huntingtin gene (htt) [>>109<<]. CAG repeat expansions in the htt gene result in an increased number of glutamine residues in the huntingtin protein (polyglutamine expansion)." . _:b418708881 "2"^^ . _:b418708738 . _:b6412157 _:b6412233 . _:b6412157 _:b6412234 . _:b418709278 . _:b6412157 _:b6412235 . _:b6412270 . . . _:b418708880 "2"^^ . _:b6412157 _:b6412236 . _:b418708749 . _:b6412157 _:b6412237 . _:b6412157 _:b6412238 . _:b6412157 _:b6412239 . _:b418708883 "2"^^ . _:b418708748 . _:b418708504 . _:b418708505 . _:b418708882 "2"^^ . _:b418708751 . _:b418708506 . _:b418708507 . _:b418708508 . _:b418708509 . _:b418708893 "2"^^ . _:b418708750 . _:b418708510 . _:b418708511 . _:b418708916 . . . _:b418709156 . _:b418708497 . _:b418708892 "2"^^ . _:b418708745 . _:b6412234 . _:b418709329 . . _:b418708498 . _:b418708499 . . _:b418708500 . _:b6412157 _:b6412256 . _:b418708895 "2"^^ . _:b418708501 . _:b418708744 . _:b418708502 . _:b6412157 _:b6412257 . _:b6412157 _:b6412258 . _:b418708503 . _:b6412157 _:b6412259 . . _:b418708712 . _:b6412157 _:b6412260 . _:b418708894 "2"^^ . _:b418708713 . _:b418708747 . _:b418708714 . _:b6412157 _:b6412261 . _:b6412157 _:b6412262 . _:b418708715 . _:b6412157 _:b6412263 . _:b418708716 . . _:b418708889 "2"^^ . _:b418708717 . _:b6412157 _:b6412264 . _:b418708746 . _:b418708718 . _:b6412157 _:b6412265 . _:b6412157 _:b6412266 . _:b418708719 . _:b6412157 _:b6412267 . _:b418708704 . _:b6412157 _:b6412268 . _:b418708888 "2"^^ . _:b418708705 . _:b418708757 . _:b418708706 . _:b6412157 _:b6412269 . _:b418708644 . _:b418708707 . _:b6412157 _:b6412270 . . _:b6412157 _:b6412271 . _:b418708708 . _:b418708755 . _:b418708891 "2"^^ . _:b418708709 . _:b418708756 . _:b418709063 . _:b418708710 . . _:b418708757 . _:b418708711 . _:b418708728 . _:b418708729 . _:b418708890 "2"^^ . . _:b418708730 . _:b418708801 . _:b418708759 . . _:b418708731 . _:b418708732 . _:b418708733 . _:b418708901 "2"^^ . _:b418708758 . _:b418708734 . _:b418708735 . _:b418708720 . . _:b418708721 . _:b418708900 "2"^^ . _:b418708753 . _:b418708722 . _:b418708723 . _:b418708724 . _:b418708725 . _:b418708903 "2"^^ . . _:b418708752 . _:b418708726 . _:b418708727 . _:b418708680 . . _:b418708902 "2"^^ . _:b418708681 . _:b418708745 . _:b418708755 . _:b418708682 . _:b418708683 . _:b418709141 . . _:b418708684 . _:b418708580 . _:b418708897 "2"^^ . _:b418708685 . _:b418708754 . _:b418708686 . _:b418708687 . _:b418708673 . _:b418708672 . _:b418708673 . _:b418708896 "2"^^ . _:b418708765 . _:b418708674 . . _:b418708675 . _:b418708676 . _:b418709074 . _:b418708677 . _:b418708899 "2"^^ . _:b418708764 . _:b418708678 . _:b418708679 . _:b6412182 "Cyclooxygenase 2 (COX2), a pro-inflammatory protein that is one of the targets of non-steroidal anti-inflammatory drugs (NSAIDs), and its homolog COX-1 [42], are elevated in AD brains [>>43<<]. Serum levels of the acute phase protein \u03B11-antichymotrypsin, which is upregulated by injury, trauma and infection, are also significantly higher in AD patients than healthy controls [44]. And clinically, a proteomic study of plasma from" . _:b418708696 . _:b418708553 . _:b418708898 "2"^^ . _:b418708697 . _:b418708767 . _:b418708698 . . _:b418708699 . _:b418708700 . _:b418708701 . _:b418709229 . _:b418708909 "2"^^ . _:b418708766 . _:b418708702 . _:b418708703 . _:b418708688 . . _:b418708908 "2"^^ . _:b418708689 . _:b418708761 . _:b418708690 . . _:b418708691 . _:b418708692 . _:b418708693 . _:b418708911 "2"^^ . _:b418708760 . _:b418708694 . _:b418708695 . _:b418708648 . _:b418708649 . _:b418708910 "2"^^ . _:b418708763 . _:b418708650 . _:b418708651 . _:b418708652 . _:b418708653 . _:b418709233 . _:b418708905 "2"^^ . _:b418708762 . _:b6412225 "in that one group reported lack of TNF receptors altered dopamine metabolism and reduced survival of dopaminergic terminals [86] and other groups reported TNF-deficient mice to have reduced sensitivity to MPTP-induced neurotoxicity [>>85<<,87]. Loss of TNF receptors versus TNF ligand during development might alter the behavior of microglia or other immune cell populations and contribute to conflicting outcomes in these studies." . _:b418708654 . _:b418708655 . _:b418708640 . _:b418708641 . _:b418708904 "2"^^ . _:b418708773 . _:b418708642 . _:b418708643 . _:b418708644 . _:b418709071 . . _:b418708907 "2"^^ . _:b418708645 . _:b418708772 . _:b418709170 . _:b418708646 . _:b418708647 . _:b418708664 . _:b418708665 . _:b418708906 "2"^^ . _:b418708775 . _:b418708666 . _:b418708667 . _:b418708668 . . _:b418708917 "2"^^ . _:b418708669 . _:b418708774 . _:b418708670 . _:b418708671 . _:b418708944 . _:b418708656 . _:b418708657 . _:b418708916 "2"^^ . . _:b418708658 . _:b418708769 . _:b418708659 . _:b418708660 . . _:b418708919 "2"^^ . _:b418708661 . _:b418708768 . _:b418709346 . _:b418708662 . _:b418708663 . _:b418709124 . . _:b418708616 . _:b418708617 . _:b418708918 "2"^^ . _:b418708771 . _:b418708618 . _:b418708619 . . _:b418708620 . _:b418708621 . _:b418708913 "2"^^ . _:b418708770 . _:b418708622 . . _:b6412215 "infused with antibodies that recognize aggregated A\u03B2 in neuritic plaques rapidly increased microglial clustering around plaques detectable by in vivo multi-photon microscopy [74] and reduced plaque burden and AD pathology in PDAPP mice [>>75<<]. Administration of antibodies specifically directed against oligomers of A\u03B2 improved learning and memory in Tg2576 mice [76]." . _:b418708623 . _:b418708608 . _:b418708609 . _:b418708912 "2"^^ . _:b418708781 . _:b418708610 . _:b418708611 . _:b418708612 . _:b418708613 . _:b418708915 "2"^^ . _:b418708780 . _:b418708855 . . _:b418708614 . _:b418708615 . _:b418708632 . _:b418708633 . _:b418708914 "2"^^ . _:b418708783 . _:b418708634 . . _:b6412161 . _:b418708635 . _:b418708636 . _:b6412156 . _:b418708637 . _:b6412232 "Given that TNF receptors are expressed in nigrostriatal dopamine neurons [93,>>94<<] and these neurons are selectively vulnerable to TNF-induced toxicity [95-99], these early genetic studies and the more recent chronic inflammation models of PD strongly implicate TNF and its downstream targets in neurotoxin- and" . _:b418708925 "2"^^ . _:b418708782 . _:b418708638 . _:b418708639 . _:b418708624 . _:b6412246 "Once symptoms have manifested, microglial activation correlates with disease severity [115,>>116<<]. In the 3-nitroproprionic acid neurotoxin model of HD in rats, treatment with Celastrol, an anti-inflammatory and antioxidant compound derived from plants, reduced striatal lesion volume [117], indicating that controlling an inflammatory" . _:b418708625 . _:b418708924 "2"^^ . _:b418708777 . _:b418708626 . _:b418708627 . _:b418708628 . _:b418709072 . _:b418708629 . _:b418708927 "2"^^ . _:b418708776 . _:b418708630 . _:b418708631 . . _:b418708926 "2"^^ . _:b418708779 . _:b418709112 . . _:b6412158 "AD in humans is unknown, mutations in Amyloid Precursor Protein (APP) or components of its processing machinery (\u03B2-secretase and \u03B3-secretase) result in overproduction of A\u03B21-40 and 1-42 peptides and are sufficient to cause disease [>>11<<-17]. Over 20 years ago, microglia were reported to localize to amyloid plaques in AD brain [18] and since then, the association between neuroinflammation and AD has been extensively investigated [7,19-24] and reviewed [19,25]." . _:b418708683 . _:b418708921 "2"^^ . _:b418708778 . _:b418708920 "2"^^ . _:b418709296 . _:b418708789 . _:b418708923 "2"^^ . _:b418708788 . _:b418708922 "2"^^ . _:b418708791 . . . _:b418708933 "2"^^ . _:b418708790 . _:b418708720 . _:b418708942 . _:b418708932 "2"^^ . _:b418708785 . _:b418708887 . . _:b418708570 . _:b418708935 "2"^^ . _:b418708784 . . _:b418708934 "2"^^ . _:b418708787 . . _:b418709315 . _:b418708929 "2"^^ . _:b418708786 . _:b418709028 . . . _:b418708519 . _:b6412254 "In addition PET imaging of ALS patients showed an increase in activated microglia in the motor cortex that correlates with upper motor neuron symptoms [>>123<<]. In some ALS disease models the presence of immune cells precedes the disease phenotype [124], and the chemokine MCP-1, a potent chemotactic stimulus for microglia [125] is elevated in the CSF of ALS patients [126], suggesting that" . _:b418708766 . _:b6412151 "Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also results in increased oxidative and nitrosative stress [>>4<<]. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Owing to the chronic" . _:b418708928 "2"^^ . _:b418708797 . . . _:b418708931 "2"^^ . _:b418709349 . _:b418708796 . . _:b418708930 "2"^^ . _:b418708799 . _:b418708859 . _:b418709350 . _:b418708941 "2"^^ . _:b418708798 . . . _:b418708940 "2"^^ . _:b418708793 . . _:b418708943 "2"^^ . _:b418708792 . . _:b418709171 . _:b418708942 "2"^^ . _:b418708795 . . _:b418708937 "2"^^ . _:b418708794 . . _:b418709338 . _:b418708639 . _:b418708936 "2"^^ . _:b418708770 . _:b418708805 . . _:b418709325 . _:b418709199 . _:b418708796 . _:b418708939 "2"^^ . _:b418708804 . _:b418708509 . _:b418708602 . _:b418708938 "2"^^ . _:b418708723 . _:b418708807 . _:b418708949 "2"^^ . . _:b418708806 . _:b418708948 "2"^^ . _:b418708801 . _:b418708951 "2"^^ . _:b418708800 . . . . _:b418708950 "2"^^ . _:b418708803 . . . _:b418708945 "2"^^ . _:b418708802 . . _:b418708944 "2"^^ . . _:b418708813 . . _:b418708947 "2"^^ . _:b418708812 . _:b418708795 . _:b418708946 "2"^^ . _:b418708815 . _:b418709015 . _:b418708957 "2"^^ . _:b418708814 . _:b418709305 . _:b418708956 "2"^^ . _:b418708809 . _:b6412260 . . _:b418708959 "2"^^ . _:b418708808 . . _:b418709070 . _:b418708958 "2"^^ . _:b418708811 . . . . _:b418708953 "2"^^ . _:b418708810 . _:b418708952 "2"^^ . _:b418708821 . . _:b418708955 "2"^^ . _:b418708820 . _:b418709241 . _:b418708909 . _:b418708954 "2"^^ . _:b418709169 . _:b418708823 . _:b418708965 "2"^^ . _:b418709079 . _:b418708822 . _:b418708964 "2"^^ . _:b418708817 . . _:b418708967 "2"^^ . . . _:b418708816 . . . _:b418708966 "2"^^ . . _:b418708819 . _:b418708930 . _:b418708961 "2"^^ . . _:b418708818 . . . . _:b418708960 "2"^^ . . _:b418708829 . _:b418708503 . . _:b418708963 "2"^^ . _:b418708828 . _:b418709279 . . _:b418708962 "2"^^ . _:b418708831 . _:b418708973 "2"^^ . _:b418708830 . _:b418708972 "2"^^ . _:b418708825 . . _:b418708975 "2"^^ . _:b418708824 . _:b418709019 . _:b418708611 . . _:b418708974 "2"^^ . _:b418708827 . _:b418708969 "2"^^ . _:b418708826 . . _:b418709054 . . _:b418708968 "2"^^ . _:b418708837 . _:b418708945 . _:b418708971 "2"^^ . _:b418708836 . _:b6412197 "In addition, there appears to be a feedback signaling loop between A\u03B2 and IL-1\u03B2: A\u03B2 can induce the production of IL-1\u03B2 [>>7<<], and the presence of IL-1\u03B2 greatly increases the secretion of cytokines IL-6 and IL-8 in response to A\u03B2 by astrocytes; in the other direction, IL-1\u03B1 and IL-1\u03B2 both upregulate the expression of APP, thus probably upregulating the" . _:b418709274 . . _:b418708970 "2"^^ . . _:b418708839 . . _:b6412181 . _:b418708981 "2"^^ . _:b418708838 . _:b418708980 "2"^^ . _:b418708833 . _:b418709044 . . _:b418708983 "2"^^ . _:b418708832 . _:b6412265 "Consistent with this idea, mSOD1 mice stimulated with LPS secrete more inflammatory mediators, including TNF [135], MCP-1, TGF-\u03B2[121] and IFN-\u03B3 [>>136<<], than control mice." . _:b418708982 "2"^^ . _:b418708835 . . _:b418709314 . _:b418708977 "2"^^ . _:b418708834 . _:b418709115 . _:b6412229 . _:b418708626 . _:b418708976 "2"^^ . _:b418708845 . _:b418709038 . _:b418708816 . _:b418708979 "2"^^ . . _:b418708844 . . _:b418708978 "2"^^ . _:b418708847 . _:b418709027 . . _:b418708989 "2"^^ . _:b418708846 . _:b418709024 . _:b418708988 "2"^^ . . _:b418708841 . _:b418708991 "2"^^ . _:b418708840 . _:b418709381 . _:b418708821 . . _:b418709276 . _:b418708990 "2"^^ . _:b418708843 . _:b418709088 . _:b418708985 "2"^^ . _:b418708842 . _:b418709368 . _:b418708860 . _:b418708984 "2"^^ . _:b6412148 . _:b418708853 . _:b418708987 "2"^^ . _:b418708852 . . _:b418708612 . . _:b418708986 "2"^^ . _:b418708855 . . . _:b418708854 . _:b418708849 . _:b418709186 . _:b418708848 . _:b418708851 . . _:b6412254 . _:b418708850 . . _:b418708861 . _:b418708860 . . _:b418709097 . _:b418708863 . _:b418709123 . _:b418708862 . . _:b418708857 . . _:b418708856 . _:b418708749 . _:b418708685 . _:b418708535 . _:b418708859 . _:b6412237 . _:b418708858 . . _:b418708869 . _:b418708868 . _:b418708871 . _:b6412233 . _:b418708870 . _:b6412244 "In brains of mutant htt carriers, microglia are activated before onset of symptoms and increased microglial activation correlates with an increased chance of developing HD symptoms in 5 years [>>114<<]. Once symptoms have manifested, microglial activation correlates with disease severity [115,116]. In the 3-nitroproprionic acid neurotoxin model of HD in rats, treatment with Celastrol, an anti-inflammatory and antioxidant compound" . _:b418708865 . _:b418708521 . _:b418708864 . _:b418708891 . . _:b418708867 . _:b418708866 . . . . _:b418708877 . _:b418708523 . . . _:b418709255 . . _:b418708876 . _:b418708879 . _:b418708684 . . _:b418708985 . . _:b418708878 . "10.1186%2F1750-1326-4-47" . . _:b418709333 . . _:b418708873 . _:b418708872 . _:b418708875 . _:b418708874 . . _:b418708885 . . _:b418709322 . _:b6412195 . _:b418708884 . . _:b418708887 . . _:b418708886 . _:b418708881 . . . _:b418708880 . _:b418708744 . _:b418708883 . _:b418709052 . . _:b418708882 . _:b418708893 . _:b418708892 . _:b418709371 . _:b418708895 . . . _:b418708894 . _:b418708628 . _:b418709023 . . _:b418708889 . . _:b418708888 . . _:b418708539 . . _:b418708891 . . _:b6412146 "overview" . . _:b418708890 . _:b6412209 . _:b418708901 . . _:b418708851 . _:b418708900 . _:b418709111 . _:b418708903 . _:b6412212 . _:b418708902 . . . _:b418709157 . . _:b418708897 . . _:b418708896 . _:b418709077 . _:b418708878 . . _:b418708899 . . _:b418708515 . . . _:b418708898 . . . _:b418708909 . _:b6412176 "The bacterial endotoxin lipopolysaccharide (LPS), a powerful inducer of inflammatory responses [36], exacerbates the appearance and severity of AD pathology in the APPV717F transgenic mouse [>>37<<], the APPswe transgenic mouse [38], and the triple-transgenic (3xTgAD) mouse [39]." . . . . _:b418708908 . _:b418708911 . _:b418708910 . . _:b418708953 . . _:b418708905 . . _:b6412198 "of IL-1\u03B2 greatly increases the secretion of cytokines IL-6 and IL-8 in response to A\u03B2 by astrocytes; in the other direction, IL-1\u03B1 and IL-1\u03B2 both upregulate the expression of APP, thus probably upregulating the production of A\u03B2 [>>59<<]. The ratio of the pro-inflammatory cytokine IL-1\u03B2 to the anti-inflammatory cytokine IL-10 is drastically elevated in the serum of AD patients, giving these patients a definite pro-inflammatory profile [60]." . _:b418708904 . _:b418708592 . _:b418709335 . . _:b6412231 "Given that TNF receptors are expressed in nigrostriatal dopamine neurons [>>93<<,94] and these neurons are selectively vulnerable to TNF-induced toxicity [95-99], these early genetic studies and the more recent chronic inflammation models of PD strongly implicate TNF and its downstream targets in neurotoxin- and" . . _:b6412185 . _:b418708524 . _:b418708907 . _:b418708827 . _:b418708837 . _:b418708906 . _:b418708584 . _:b418708917 . _:b418709056 . . _:b418708916 . _:b418708919 . . _:b418708918 . . _:b418708913 . _:b418709251 . _:b418708912 . . _:b418708915 . . . . _:b418708914 . . . _:b6412260 . _:b418708925 . _:b418708924 . _:b418709144 . _:b418708706 . _:b418708927 . _:b418709227 . _:b418708926 . _:b418708788 . _:b418708921 . _:b418708920 . _:b418709188 . _:b418708923 . _:b418709049 . _:b418708867 . _:b6412258 "In addition, the levels of general markers of inflammation in the serum of ALS patients correlate positively with the severity of their disability [>>127<<]. While multiple genetic loci have been identified as causal in familial forms of ALS, 20% of familial cases involve a gain of function mutation in Cu/Zn superoxide dismutase I (SOD1) [128]. In addition to the well-established role of" . _:b418708517 . _:b418709075 . _:b418708682 . _:b418708922 . _:b418708933 . . _:b418709210 . _:b418708932 . _:b418709234 . . _:b418708935 . _:b418708934 . _:b418709008 . _:b418708929 . . . _:b418708928 . . _:b418708931 . _:b418708930 . _:b6412176 . _:b418708941 . _:b418708556 . _:b6412226 "in that one group reported lack of TNF receptors altered dopamine metabolism and reduced survival of dopaminergic terminals [86] and other groups reported TNF-deficient mice to have reduced sensitivity to MPTP-induced neurotoxicity [85,>>87<<]. Loss of TNF receptors versus TNF ligand during development might alter the behavior of microglia or other immune cell populations and contribute to conflicting outcomes in these studies." . _:b418708940 . . _:b418708943 . . _:b418708971 . _:b6412208 "A\u03B2 vaccinations were also found successful in reducing A\u03B2 levels in two non-human primates, the rhesus monkey [68] and the Caribbean vervet [>>69<<]. A clinical trial of A\u03B242 vaccinations was undertaken by Elan Pharmaceuticals in AD patients, and the immunizations resulted in significant clearance of A\u03B2 and plaque removal in some of the patients [70,71], as well as a slowing of the" . _:b418708942 . _:b418708507 . _:b418708937 . . _:b6412225 . _:b418708936 . . . _:b418708567 . . _:b418708939 . _:b6412252 "Areas where degenerating motor neurons are present in both ALS patients and mouse models are marked by the presence of cytokines and immune cells, including T cells, activated microglia, and astrocytes [>>121<<,122]. In addition PET imaging of ALS patients showed an increase in activated microglia in the motor cortex that correlates with upper motor neuron symptoms [123]. In some ALS disease models the presence of immune cells precedes the" . _:b418708938 . _:b418709040 . _:b418709268 . _:b418708949 . . _:b418708948 . . _:b418708951 . _:b418708500 . . _:b418708950 . _:b418709131 . . _:b418708945 . _:b418708624 . . _:b418708944 . _:b418708522 . _:b418708947 . _:b418709059 . _:b418708946 . _:b418709125 . _:b418708957 . _:b418709147 . . . _:b418709174 . . _:b418708956 . . _:b418708915 . _:b6412222 . _:b418708959 . _:b418708835 . _:b418708958 . . . . _:b418708953 . _:b418708845 . _:b418708972 . _:b418708952 . _:b418709014 . _:b418708568 . _:b418708955 . _:b418708544 . _:b418708989 . . _:b418708954 . _:b418708965 . . _:b418708964 . _:b418709218 . _:b418708967 . _:b418709184 . _:b418708747 . _:b418708966 .