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Statements

Subject Item: n4:20798769
rdf:type: n3:RelevantPaper n3:ReferencePaper n3:CitationPaper
rdfs:seeAlso: n7:0 n9:10.4061%2F2010%2F732806 n10:0 n11:20798769
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n3:pmcid: PMC0
bibo:doi: 10.4061%2F2010%2F732806
n2:contains: _:vb8570506 _:vb8570416 _:vb8570424 _:vb8570430 _:vb8570472 _:vb8570476 _:vb8570448 _:vb8570459 _:vb8570440

Subject Item: _:vb8570416
rdf:type: n2:Section
dc:title: introduction
n2:contains: _:vb8570420 _:vb8570421 _:vb8570422 _:vb8570423 _:vb8570417 _:vb8570418 _:vb8570419

Subject Item: _:vb8570417
rdf:type: n3:Context
rdf:value: Also brains of “healthy aged” individuals show concentrations of serum markers related to inflammation, homocysteine and cholesterol homeostasis are associated with cognitive functioning in the nondemented healthy aging population [>>2<<]. In the AD pathology, these aging-related inflammatory processes are increased. The suggestion that inflammation may participate in AD first came up more than two decades ago. As several clinical trials have shown a beneficial effect for
n3:mentions: n4:12629905

Subject Item: _:vb8570418
rdf:type: n3:Context
rdf:value: Because many investigators have concluded that neuroinflammation contributes to neuronal damage in the brain during AD [3, >>4<<], the use of anti-inflammatory drugs as a possible treatment option has been widely investigated [5–7].
n3:mentions: n4:10858586

Subject Item: _:vb8570419
rdf:type: n3:Context
rdf:value: Because many investigators have concluded that neuroinflammation contributes to neuronal damage in the brain during AD [3, 4], the use of anti-inflammatory drugs as a possible treatment option has been widely investigated [>>5<<–7]. Anti-inflammatory therapy has therefore been credited as a strategy for reducing the risk or slowing the progression of AD. However, the results of these studies remain inconsistent [8].
n3:mentions: n4:18003940 n4:10851364 n4:11794217

Subject Item: _:vb8570420
rdf:type: n3:Context
rdf:value: Anti-inflammatory therapy has therefore been credited as a strategy for reducing the risk or slowing the progression of AD. However, the results of these studies remain inconsistent [>>8<<].
n3:mentions: n4:14718699

Subject Item: _:vb8570421
rdf:type: n3:Context
rdf:value: T cell deficient mice show impaired learning abilities, which can be reversed with T cell substitution [>>9<<, 10].
n3:mentions: n4:15141078

Subject Item: _:vb8570422
rdf:type: n3:Context
rdf:value: T cell deficient mice show impaired learning abilities, which can be reversed with T cell substitution [9, >>10<<].
n3:mentions: n4:16415867

Subject Item: _:vb8570423
rdf:type: n3:Context
rdf:value: In this activated state, microglia produce various proinflammatory cytokines and other immune mediators that create a neurotoxic milieu leading to disease progression [>>4<<, 11].
n3:mentions: n4:10858586

Subject Item: _:vb8570424
rdf:type: n2:Section
dc:title: conclusion
n2:contains: _:vb8570428 _:vb8570429 _:vb8570425 _:vb8570426 _:vb8570427

Subject Item: _:vb8570425
rdf:type: n3:Context
rdf:value: Many lines of evidence show that Aβ-induced neuroinflammation is an early event in neurodegeneration of AD [>>86<<], as increases in microglial activation has been observed in very early stages of AD and disappeared over time [37].
n3:mentions: n4:16369931

Subject Item: _:vb8570426
rdf:type: n3:Context
rdf:value: Many lines of evidence show that Aβ-induced neuroinflammation is an early event in neurodegeneration of AD [86], as increases in microglial activation has been observed in very early stages of AD and disappeared over time [>>37<<]. The fact that neuroinflammation occurs very early in AD could explain why anti-inflammatory treatment seems to be most efficient as preventive or early treatment. There are several reasons why an early use of NSAIDs is superior to a
n3:mentions: n4:12498966

Subject Item: _:vb8570427
rdf:type: n3:Context
rdf:value: There are several reasons why an early use of NSAIDs is superior to a late one: Cox-expression in the brain decreases over time in AD brains [>>87<<]. And the CSF PG E2 levels in patients with Alzheimer's disease were high when their short-term memory scores were just below those of controls, but were low in later stages of the disease. These findings further support that inflammatory
n3:mentions: n4:11754989

Subject Item: _:vb8570428
rdf:type: n3:Context
rdf:value: Especially the drug selection seems essential as some NSAIDs have recently been shown to increase Aβ-42 levels [>>77<<]. It also has to be noted that the protective effects of NSAIDs may be via non-COX-inhibitory mechanisms, such as lowering of Aβ levels and activation of the peroxisome proliferator-activated receptor-[gamma] [89] and these
n3:mentions: n4:19066416

Subject Item: _:vb8570429
rdf:type: n3:Context
rdf:value: It also has to be noted that the protective effects of NSAIDs may be via non-COX-inhibitory mechanisms, such as lowering of Aβ levels and activation of the peroxisome proliferator-activated receptor-[gamma] [>>89<<] and these non-COX-dependent mechanisms might be differentially distributed among COX-inhibitors.
n3:mentions: n4:12849425

Subject Item: _:vb8570430
rdf:type: n2:Section
dc:title: characteristics of neuroinflammation in ad
n2:contains: _:vb8570431 _:vb8570436 _:vb8570437 _:vb8570438 _:vb8570439 _:vb8570432 _:vb8570433 _:vb8570434 _:vb8570435

Subject Item: _:vb8570431
rdf:type: n3:Context
rdf:value: One argument is that increased microglial activation has been shown in regions associated with Aβ deposition [>>12<<]. Upregulated inﬂammatory mechanisms colocalize in the AD brain with those regions that exhibit high levels of AD pathology (e.g. frontal and limbic cortex) and are minimal in brain regions with low AD pathologic susceptibility (e.g.
n3:mentions: n4:18786637

Subject Item: _:vb8570432
rdf:type: n3:Context
rdf:value: inﬂammatory mechanisms colocalize in the AD brain with those regions that exhibit high levels of AD pathology (e.g. frontal and limbic cortex) and are minimal in brain regions with low AD pathologic susceptibility (e.g. cerebellum) [>>13<<].
n3:mentions: n4:11193789

Subject Item: _:vb8570433
rdf:type: n3:Context
rdf:value: This is indicated by the presence of antigens associated with microglia activation and inflammatory mediators, such as factors of the complement system, cytokines, and free radicals [>>14<<].
n3:mentions: n4:12563281

Subject Item: _:vb8570434
rdf:type: n3:Context
rdf:value: For interleukin-6 (IL) and related markers of this proinflammatory cytokine system, decreases were observed in the demented population [>>15<<, 16]. It is discussed, however, whether this decrease is related to further psychopathological symptoms such as depression [16]. On the other hand, IL-6 has also neuroprotective properties and decreased IL-6 might be associated with
n3:mentions: n4:18303264

Subject Item: _:vb8570435
rdf:type: n3:Context
rdf:value: For interleukin-6 (IL) and related markers of this proinflammatory cytokine system, decreases were observed in the demented population [15, >>16<<]. It is discussed, however, whether this decrease is related to further psychopathological symptoms such as depression [16]. On the other hand, IL-6 has also neuroprotective properties and decreased IL-6 might be associated with decreased
n3:mentions: n4:10025579

Subject Item: _:vb8570436
rdf:type: n3:Context
rdf:value: It is discussed, however, whether this decrease is related to further psychopathological symptoms such as depression [>>16<<]. On the other hand, IL-6 has also neuroprotective properties and decreased IL-6 might be associated with decreased neuroprotection [17].
n3:mentions: n4:10025579

Subject Item: _:vb8570437
rdf:type: n3:Context
rdf:value: On the other hand, IL-6 has also neuroprotective properties and decreased IL-6 might be associated with decreased neuroprotection [>>17<<].
n3:mentions: n4:19061939

Subject Item: _:vb8570438
rdf:type: n3:Context
rdf:value: Their level of inflammatory markers is signifcantly greater than levels of nondemented patients, but dramatically less than AD patients [>>18<<]. These findings further strengthen that an inflammation is a necessity for clinical symptoms of AD.
n3:mentions: n4:8858005

Subject Item: _:vb8570439
rdf:type: n3:Context
rdf:value: For instance, complement fxation and lysis of neurites could be demonstrated ultrastructurally in Alzheimer's disease cortex, but in contrast it was only very weakly detected in nondemented elderly cortex under the same conditions [>>19<<].
n3:mentions: n4:9330973

Subject Item: _:vb8570440
rdf:type: n2:Section
dc:title: controversy: do activated microglia cause neuroprotection or -degeneration in the ad brain?
n2:contains: _:vb8570444 _:vb8570445 _:vb8570446 _:vb8570447 _:vb8570441 _:vb8570442 _:vb8570443

Subject Item: _:vb8570441
rdf:type: n3:Context
rdf:value: Del Rio Hortega determined in 1927 that microglia belong to a distinct glial cell type apart from astrocytes and oligodendrocytes [>>20<<]. Since the 1970s there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders (including AD) by releasing
n3:mentions: n4:8354484

Subject Item: _:vb8570442
rdf:type: n3:Context
rdf:value: and participate in initiation and progression of neurological disorders (including AD) by releasing potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases, and complement proteins [>>21<<]. This means that their phagocytic function can be beneficial while their inflammation related functions might be detrimental.
n3:mentions: n4:17180163

Subject Item: _:vb8570443
rdf:type: n3:Context
rdf:value: Several studies give evidence for an increased number of morphologically reactive microglia in AD brains compared to nondemented individuals [>>22<<, 23]. The location of these reactive microglia has been indentified directly around plaques [24].
n3:mentions: n4:2117395

Subject Item: _:vb8570444
rdf:type: n3:Context
rdf:value: Several studies give evidence for an increased number of morphologically reactive microglia in AD brains compared to nondemented individuals [22, >>23<<]. The location of these reactive microglia has been indentified directly around plaques [24].
n3:mentions: n4:1698655

Subject Item: _:vb8570445
rdf:type: n3:Context
rdf:value: The location of these reactive microglia has been indentified directly around plaques [>>24<<]. This finding has been verified in a recent imaging study, which showed increased microglial activation in regions associated with amyloid deposition [12]. Up to now, the exact timing of this association could not be identified.
n3:mentions: n4:2097581

Subject Item: _:vb8570446
rdf:type: n3:Context
rdf:value: This finding has been verified in a recent imaging study, which showed increased microglial activation in regions associated with amyloid deposition [>>12<<]. Up to now, the exact timing of this association could not be identified. Microgliosis might be an early component of the disease process and not necessarily dependent upon Aβ plaque interaction as a stimulus. What is known so far is
n3:mentions: n4:18786637

Subject Item: _:vb8570447
rdf:type: n3:Context
rdf:value: What is known so far is that activation of microglia by Aβ fibrils is associated with a chemotactic response and extensive clustering of microglia around Aβ plaques in the AD brain [>>25<<]. These findings indicate the prominent role of microglial cells in AD. Nonetheless it remains unclear, whether their functions are beneficial or detrimental.
n3:mentions: n4:11424194

Subject Item: _:vb8570448
rdf:type: n2:Section
dc:title: neuroprotective properties of microglia in ad
n2:contains: _:vb8570452 _:vb8570453 _:vb8570454 _:vb8570455 _:vb8570449 _:vb8570450 _:vb8570451 _:vb8570456 _:vb8570457 _:vb8570458

Subject Item: _:vb8570449
rdf:type: n3:Context
rdf:value: Therefore most of the microglia that were associated with plaques in the mouse brain came from the bone marrow [>>26<<]. Furthermore it has been suggested that newly recruited microglia have different phagocytotic properties than intrinsic microglia, which is important for Aβ elimination. Lysosmes from the macrophage cell line are more acidic than those
n3:mentions: n4:15084516

Subject Item: _:vb8570450
rdf:type: n3:Context
rdf:value: Lysosmes from the macrophage cell line are more acidic than those of microglial lysosomes [>>27<<]. This indicates that microglia derived from the periphery might be more efficient in eliminating Aβ than brain microglia. Furthermore, phagocytic activity of microglia is dampened by proinflammatory cytokines like tumor necrosis factor α
n3:mentions: n4:17314396

Subject Item: _:vb8570451
rdf:type: n3:Context
rdf:value: Furthermore, phagocytic activity of microglia is dampened by proinflammatory cytokines like tumor necrosis factor α (TNF) [>>28<<]. These findings show that microglia that are committed to an inflammatory response may have a lower phagocytotic capacity, than newly recruited microglia. In mouse models of AD it could be demonstrated that anti-inflammatory drugs like
n3:mentions: n4:16148231

Subject Item: _:vb8570452
rdf:type: n3:Context
rdf:value: In mouse models of AD it could be demonstrated that anti-inflammatory drugs like minocycline improve cognitive functions and reduce the activation of microglial cells but do not alter the Aβ plaques deposition and distribution [>>29<<]. Seabrook et al. showed in amyloid precursor protein transgenic mice an age dependent effect of minocycline:
n3:mentions: n4:17376966

Subject Item: _:vb8570453
rdf:type: n3:Context
rdf:value: Seabrook et al. showed in amyloid precursor protein transgenic mice an age dependent effect of minocycline: in young animals the drug increased the amyloid load indicating a beneficial effect of microglia in clearing amyloid [>>30<<]. Not only for AD minocycline was investigated as a potential treatment, also in schizophrenia an add-on therapy with minocycline appeared to be effective on the cognitive performance by reducing a broad range of psychotic symptoms [31].
n3:mentions: n4:16534778

Subject Item: _:vb8570454
rdf:type: n3:Context
rdf:value: Not only for AD minocycline was investigated as a potential treatment, also in schizophrenia an add-on therapy with minocycline appeared to be effective on the cognitive performance by reducing a broad range of psychotic symptoms [>>31<<]. On the other hand an additional mechanism might help microglia cells with the elimination process. Transforming growth factor-β 1 has been demonstrated to promote microglial Aβ clearance and reduce plaque burden [32]. This could support
n3:mentions: n4:19855900

Subject Item: _:vb8570455
rdf:type: n3:Context
rdf:value: Microglial cells can increase their capacity to take up glutamate upon stimulation with lipopolysaccaride (LPS) over a mechanism that is TNFα dependent [>>33<<]. For AD this microglial function could be relevant because memantine (the NMDA receptor antagonist) has been shown to improve cognition, function (activities of daily living), agitation, and delusions in AD patients [34]. Taken this
n3:mentions: n4:15789431

Subject Item: _:vb8570456
rdf:type: n3:Context
rdf:value: For AD this microglial function could be relevant because memantine (the NMDA receptor antagonist) has been shown to improve cognition, function (activities of daily living), agitation, and delusions in AD patients [>>34<<]. Taken this together, microglial cells are important for the control of glutamate levels and might therefore contribute to neuronal survival. There is also evidence that microglia are capable of secreting neurotrophic or neuron survival
n3:mentions: n4:20021448

Subject Item: _:vb8570457
rdf:type: n3:Context
rdf:value: There is also evidence that microglia are capable of secreting neurotrophic or neuron survival factors (e.g. nerve growth factor and neurotrophin 3) upon activation via inflammation or injury [>>35<<].
n3:mentions: n4:15954124

Subject Item: _:vb8570458
rdf:type: n3:Context
rdf:value: This is in line with the finding that microglia are not just “resting” but have active sensor and versatile functions [>>36<<].
n3:mentions: n4:17965659

Subject Item: _:vb8570459
rdf:type: n2:Section
dc:title: microgliaâare they responsible for neurodestruction and -degeneration?
n2:contains: _:vb8570460 _:vb8570461 _:vb8570462 _:vb8570463 _:vb8570464 _:vb8570465 _:vb8570466 _:vb8570467 _:vb8570468 _:vb8570469 _:vb8570470 _:vb8570471

Subject Item: _:vb8570460
rdf:type: n3:Context
rdf:value: This increase surprisingly disappeared over time [>>37<<]. The suggestion of Vehmas et al. strengthens the assumption that microglial activation begins early in disease progression [37].
n3:mentions: n4:12498966

Subject Item: _:vb8570461
rdf:type: n3:Context
rdf:value: The suggestion of Vehmas et al. strengthens the assumption that microglial activation begins early in disease progression [>>37<<]. This could be a hint that microglia initially try to eliminate Aβ, but over time of the disease fail and therefore decrease their activity. Alternatively, the microglial role in AD could be detrimental and they initiate the underlying
n3:mentions: n4:12498966

Subject Item: _:vb8570462
rdf:type: n3:Context
rdf:value: Also the chemotactic functions of Aβ to attract microglia contribute further to the ongoing inflammatory process [>>25<<]. The ratio of the proinflammatory cytokine IL-1β to the anti-inflammatory cytokine IL-10 is drastically elevated in the serum of AD patients, giving these patients a definite long-term proinflammatory profile [38], indicating a chronic
n3:mentions: n4:11424194

Subject Item: _:vb8570463
rdf:type: n3:Context
rdf:value: The ratio of the proinflammatory cytokine IL-1β to the anti-inflammatory cytokine IL-10 is drastically elevated in the serum of AD patients, giving these patients a definite long-term proinflammatory profile [>>38<<], indicating a chronic neuroinflammatory state of the CNS.
n3:mentions: n4:11162920

Subject Item: _:vb8570464
rdf:type: n3:Context
rdf:value: There is also the emerging idea that an inflamed CNS environment may influence the ability of microglia to contribute to plaque deposition rather than plaque removal [>>28<<]. This strongly suggests that the microenvironment of the brain can influence whether microglia perform beneficial or deleterious functions in pathophysiological states.
n3:mentions: n4:16148231

Subject Item: _:vb8570465
rdf:type: n3:Context
rdf:value: This means that microglia cells functionally adapt to their environment [>>36<<]. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity [39].
n3:mentions: n4:17965659

Subject Item: _:vb8570466
rdf:type: n3:Context
rdf:value: Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity [>>39<<]. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis, but eventually also for the development of targeted anti-inflammatory therapies that might
n3:mentions: n4:19359988

Subject Item: _:vb8570467
rdf:type: n3:Context
rdf:value: imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis, but eventually also for the development of targeted anti-inflammatory therapies that might diminish the progression of the disease [>>21<<].
n3:mentions: n4:17180163

Subject Item: _:vb8570468
rdf:type: n3:Context
rdf:value: In addition, activated microglia release the excitotoxin quinolinic acid [>>40<<], and microglia activated by AD plaques produce an apparently novel amine that evokes fulminant excitotoxicity [41].
n3:mentions: n4:9080423

Subject Item: _:vb8570469
rdf:type: n3:Context
rdf:value: In addition, activated microglia release the excitotoxin quinolinic acid [40], and microglia activated by AD plaques produce an apparently novel amine that evokes fulminant excitotoxicity [>>41<<]. One interesting implication of an excitotoxic contribution to inﬂammatory mechanisms is the potential for limited damage to functional cellular compartments.
n3:mentions: n4:7655344

Subject Item: _:vb8570470
rdf:type: n3:Context
rdf:value: Some of their products like 3-hydroxyanthralinic acid (which is—like quinolinic acid—one of the downstream products of the tryptophan metabolism) exert antioxidant and anti-inflammatory functions [>>42<<, 43]. Therefore the balance of these products that result from activated microglia is important for the inflammation process.
n3:mentions: n4:16959377

Subject Item: _:vb8570471
rdf:type: n3:Context
rdf:value: Some of their products like 3-hydroxyanthralinic acid (which is—like quinolinic acid—one of the downstream products of the tryptophan metabolism) exert antioxidant and anti-inflammatory functions [42, >>43<<]. Therefore the balance of these products that result from activated microglia is important for the inflammation process.
n3:mentions: n4:8955104

Subject Item: _:vb8570472
rdf:type: n2:Section
dc:title: the role of cox inhibitors in neurodegeneration
n2:contains: _:vb8570473 _:vb8570474 _:vb8570475

Subject Item: _:vb8570473
rdf:type: n3:Context
rdf:value: The peroxidase activity also results in the production of free radicals, which are in part utilized by COX itself [>>44<<]. Although NSAIDs may have other effects as well, it is generally assumed that their primary mechanism of action is by competitive inhibition of COX activity, thereby reducing the production of inﬂammatory prostaglandins from
n3:mentions: n4:8969167

Subject Item: _:vb8570474
rdf:type: n3:Context
rdf:value: COX not only helps mediate production of prostaglandins and other inﬂammatory factors, it is itself upregulated by pro-inﬂammatory mediators [>>44<<].
n3:mentions: n4:8969167

Subject Item: _:vb8570475
rdf:type: n3:Context
rdf:value: These mechanisms include oxidative damage, direct cytotoxicity, and induction of destructive inflammatory mechanisms; efforts have been directed at the control of each of these processes [>>45<<]. See Figure 1 for the involvment of COX in the AD pathology.
n3:mentions: n4:9153159

Subject Item: _:vb8570476
rdf:type: n2:Section
dc:title: possible mechanisms of action of nsaid in ad
n2:contains: _:vb8570487 _:vb8570480 _:vb8570481 _:vb8570482 _:vb8570483 _:vb8570492 _:vb8570493 _:vb8570494 _:vb8570495 _:vb8570488 _:vb8570489 _:vb8570490 _:vb8570491 _:vb8570477 _:vb8570478 _:vb8570479 _:vb8570500 _:vb8570501 _:vb8570502 _:vb8570503 _:vb8570496 _:vb8570497 _:vb8570498 _:vb8570499 _:vb8570504 _:vb8570505 _:vb8570484 _:vb8570485 _:vb8570486

Subject Item: _:vb8570477
rdf:type: n3:Context
rdf:value: Although in vivo the majority of COX-2 appears to be made in neurons, COX-2 was also seen in rat astrocytes and microglia [>>46<<]. It has been demonstrated that COX-inhibiting NSAIDs reduce microglial activation following infusion of Aβ in rats [47]. Neuronal stress, such as ischaemia and excitotoxicity, is associated with strong upregulation of neuronal COX-2
n3:mentions: n4:10049531

Subject Item: _:vb8570478
rdf:type: n3:Context
rdf:value: It has been demonstrated that COX-inhibiting NSAIDs reduce microglial activation following infusion of Aβ in rats [>>47<<]. Neuronal stress, such as ischaemia and excitotoxicity, is associated with strong upregulation of neuronal COX-2 expression. This suggests that COX-2 is involved in neurotoxic mechanisms and may therefore represent a target for drug
n3:mentions: n4:10588578

Subject Item: _:vb8570479
rdf:type: n3:Context
rdf:value: This suggests that COX-2 is involved in neurotoxic mechanisms and may therefore represent a target for drug therapy in the treatment of AD [>>48<<, 49].
n3:mentions: n4:9064608

Subject Item: _:vb8570480
rdf:type: n3:Context
rdf:value: This suggests that COX-2 is involved in neurotoxic mechanisms and may therefore represent a target for drug therapy in the treatment of AD [48, >>49<<].
n3:mentions: n4:9168834

Subject Item: _:vb8570481
rdf:type: n3:Context
rdf:value: Neuronal COX-2 is upregulated in response to exposure to Aβ [>>50<<], and focal increases in COX-2 have been shown in the region of amyloid plaques in double transgenic mice carrying genes that encode both mutant APP and mutant presenilin 1 [51].
n3:mentions: n4:9740394

Subject Item: _:vb8570482
rdf:type: n3:Context
rdf:value: COX-2 is upregulated in response to exposure to Aβ [50], and focal increases in COX-2 have been shown in the region of amyloid plaques in double transgenic mice carrying genes that encode both mutant APP and mutant presenilin 1 [>>51<<]. Many studies seem to show that COX-2 inhibition confers neuroprotection [52–55].
n3:mentions: n4:11290552

Subject Item: _:vb8570483
rdf:type: n3:Context
rdf:value: Many studies seem to show that COX-2 inhibition confers neuroprotection [>>52<<–55]. Some studies have revealed an upregulation of neuronal COX-2 in the brains of patients with AD [56, 57], though this has not been a universal finding [58, 59]. One explanation for the variation of COX expression is the short
n3:mentions: n4:11168565 n4:11026726 n4:10773011 n4:11588328

Subject Item: _:vb8570484
rdf:type: n3:Context
rdf:value: Some studies have revealed an upregulation of neuronal COX-2 in the brains of patients with AD [>>56<<, 57], though this has not been a universal finding [58, 59].
n3:mentions: n4:10366679

Subject Item: _:vb8570485
rdf:type: n3:Context
rdf:value: Some studies have revealed an upregulation of neuronal COX-2 in the brains of patients with AD [56, >>57<<], though this has not been a universal finding [58, 59].
n3:mentions: n4:11255454

Subject Item: _:vb8570486
rdf:type: n3:Context
rdf:value: Some studies have revealed an upregulation of neuronal COX-2 in the brains of patients with AD [56, 57], though this has not been a universal finding [>>58<<, 59]. One explanation for the variation of COX expression is the short half-life of COX-2 transcripts or individual variability of inflammatory-related processes.
n3:mentions: n4:9452008

Subject Item: _:vb8570487
rdf:type: n3:Context
rdf:value: Some studies have revealed an upregulation of neuronal COX-2 in the brains of patients with AD [56, 57], though this has not been a universal finding [58, >>59<<]. One explanation for the variation of COX expression is the short half-life of COX-2 transcripts or individual variability of inflammatory-related processes.
n3:mentions: n4:8892355

Subject Item: _:vb8570488
rdf:type: n3:Context
rdf:value: Another principle of how NSAIDs could act, comes from the finding that prostaglandin E2 levels are elevated in patients with AD, especially in early stages of the disease [>>60<<]. Therefore NSAIDs blocking prostaglandin E2 synthesis might be beneficial.
n3:mentions: n4:10534257

Subject Item: _:vb8570489
rdf:type: n3:Context
rdf:value: This issue is further strengthened by glial culture studies indicating that prostaglandins, particularly prostaglandin E, alter the production of several inﬂammation-related molecules, including IL-6, chemokines, and APP [>>61<<–63].
n3:mentions: n4:9003059 n4:9920657 n4:9449430

Subject Item: _:vb8570490
rdf:type: n3:Context
rdf:value: For example, several of the prostanoid products of arachidonate metabolism potentiate glutamate excitotoxicity, and COX-2 overexpressing transgenic mice exhibit increased neuronal susceptibility to excitotoxic insult [>>64<<].
n3:mentions: n4:10487857

Subject Item: _:vb8570491
rdf:type: n3:Context
rdf:value: Some of the previously mentioned studies of COX in ischemia also suggest that intraneuronal COX-2 levels may contribute to neuronal death by production of free radicals [>>65<<]. In addition, increased COX-2 levels in AD neurons may directly damage neurons or increase their vulnerability to other detrimental processes occurring in AD brain [65].
n3:mentions: n4:9778144

Subject Item: _:vb8570492
rdf:type: n3:Context
rdf:value: In addition, increased COX-2 levels in AD neurons may directly damage neurons or increase their vulnerability to other detrimental processes occurring in AD brain [>>65<<]. Thus, NSAIDs actions to inhibit COX-mediated production of apoptotic factors by neurons could be one of the mechanisms by which these drugs seem to exert benefcial effects in AD.
n3:mentions: n4:9778144

Subject Item: _:vb8570493
rdf:type: n3:Context
rdf:value: Another non-COX-dependent mechanism of NSAIDs is to attenuate inﬂammatory processes in a manner by directly activating the peroxisome proliferator-activated receptor gamma (PPARγ), a receptor and nuclear transcription factor [>>66<<–68]. PPARγ is a member of the orphan nuclear receptor family and in cells of monocytic lineage, including microglia, acts to suppress the expression of a broad range of proinﬂammatory genes [66, 68].
n3:mentions: n4:9422508 n4:9422509 n4:9013583

Subject Item: _:vb8570494
rdf:type: n3:Context
rdf:value: PPARγ is a member of the orphan nuclear receptor family and in cells of monocytic lineage, including microglia, acts to suppress the expression of a broad range of proinﬂammatory genes [>>66<<, 68]. Some NSAIDs act as PPARγ agonists, directly binding to it and initiating its transcriptional activity. Activation of PPARγ inhibits the Aβ-stimulated activation of microglia and monocytes and their secretion of proinﬂammatory and
n3:mentions: n4:9422509

Subject Item: _:vb8570495
rdf:type: n3:Context
rdf:value: PPARγ is a member of the orphan nuclear receptor family and in cells of monocytic lineage, including microglia, acts to suppress the expression of a broad range of proinﬂammatory genes [66, >>68<<]. Some NSAIDs act as PPARγ agonists, directly binding to it and initiating its transcriptional activity. Activation of PPARγ inhibits the Aβ-stimulated activation of microglia and monocytes and their secretion of proinﬂammatory and
n3:mentions: n4:9422508

Subject Item: _:vb8570496
rdf:type: n3:Context
rdf:value: For example, PPARγ agonists act to inhibit the Aβ-stimulated expression of IL-6 and TNF-alpha [>>69<<], by microglia and monocytes, and to prevent Aβ-mediated conversion of microglia into an activated phenotype [70].
n3:mentions: n4:9920656

Subject Item: _:vb8570497
rdf:type: n3:Context
rdf:value: For example, PPARγ agonists act to inhibit the Aβ-stimulated expression of IL-6 and TNF-alpha [69], by microglia and monocytes, and to prevent Aβ-mediated conversion of microglia into an activated phenotype [>>70<<].
n3:mentions: n4:10632585

Subject Item: _:vb8570498
rdf:type: n3:Context
rdf:value: A further underlying mechanism of AD pathology is oxidative stress [>>71<<, 72]. Activated microglial cells are known to release ROS, which might possibly cause this oxidative stress.
n3:mentions: n4:20084018

Subject Item: _:vb8570499
rdf:type: n3:Context
rdf:value: HO-1 was found to be colocalized to senile plaques, neurofibrillary tangles, and corpora amylacea [>>73<<]. It is widely accepted that a moderate activation of heme catabolism is neuroprotective and contributes to degradation of neurotoxic protein aggregates. Regulatory interactions between HO-1 and COX pathways have also been reported [74].
n3:mentions: n4:19457088

Subject Item: _:vb8570500
rdf:type: n3:Context
rdf:value: Regulatory interactions between HO-1 and COX pathways have also been reported [>>74<<]. However, experimental observations indicate that the extent of HO-1 induction may be critical because excessive heme degradation may result in toxic levels of carbon monoxide, bilirubin and iron. Pharmacological modulation of HO-1
n3:mentions: n4:14529552

Subject Item: _:vb8570501
rdf:type: n3:Context
rdf:value: Pharmacological modulation of HO-1 levels in the brain shows promising results in models of AD and Parkinson's disease [>>75<<].
n3:mentions: n4:18289070

Subject Item: _:vb8570502
rdf:type: n3:Context
rdf:value: It has been shown that daily doses of NSAIDs increase circulating levels of antioxidants [>>76<<]. In a rat model of AD it was suggested that treatment with a COX-2 inhibitor reduces oxidative stress and might therefore be beneficial for the course of AD [77].
n3:mentions: n4:9202422

Subject Item: _:vb8570503
rdf:type: n3:Context
rdf:value: In a rat model of AD it was suggested that treatment with a COX-2 inhibitor reduces oxidative stress and might therefore be beneficial for the course of AD [>>77<<].
n3:mentions: n4:19066416

Subject Item: _:vb8570504
rdf:type: n3:Context
rdf:value: As another mechanism it has been suggested that NSAIDs directly affect amyloid pathology in the brain by reducing Aβ-42 peptide levels over the gamma-secretase activity independently of COX activity [>>78<<]. Weggen et al. reported that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ-42 peptide produced from a variety of cultured cells by as much as 80% [79].
n3:mentions: n4:20015011

Subject Item: _:vb8570505
rdf:type: n3:Context
rdf:value: Weggen et al. reported that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ-42 peptide produced from a variety of cultured cells by as much as 80% [>>79<<]. However, for some NSAIDs the lowering effect of Aβ-42 could not be shown; instead, an increase in Aβ-42 levels was observed [80]. The underlying mechanism of how NSAIDs decrease Aβ-42 was clarified by Lleo et al., who demonstrated that
n3:mentions: n4:11700559

Subject Item: _:vb8570506
rdf:type: n2:Section
dc:title: anti-inflammatory treatment studies in ad
n2:contains: _:vb8570508 _:vb8570509 _:vb8570510 _:vb8570511 _:vb8570507 _:vb8570512 _:vb8570513 _:vb8570514

Subject Item: _:vb8570507
rdf:type: n3:Context
rdf:value: A prospective cohort study with 6989 subjects showed that long-term use of NSAIDs protects against AD but not against vascular dementia [>>5<<]. More recently, Szekely et al. provided very similar findings:
n3:mentions: n4:11794217

Subject Item: _:vb8570508
rdf:type: n3:Context
rdf:value: This study was done with over 3,000 subjects aged 65 years and older [>>6<<]. Not only selective COX-2 inhibitors were shown to be associated with decreased risk of AD; a reduced occurrence of AD could also be demonstrated for the use of the COX-1 inhibitor aspirin [7].
n3:mentions: n4:18003940

Subject Item: _:vb8570509
rdf:type: n3:Context
rdf:value: Not only selective COX-2 inhibitors were shown to be associated with decreased risk of AD; a reduced occurrence of AD could also be demonstrated for the use of the COX-1 inhibitor aspirin [>>7<<]. A meta-analysis of 17 epidemiological studies yielded strong, generally consistent, statistical evidence that NSAID and steroid use is associated with reduced risk of AD [82]. Vlad et al. investigated 49,349 patients with AD and 196,850
n3:mentions: n4:10851364

Subject Item: _:vb8570510
rdf:type: n3:Context
rdf:value: A meta-analysis of 17 epidemiological studies yielded strong, generally consistent, statistical evidence that NSAID and steroid use is associated with reduced risk of AD [>>82<<]. Vlad et al. investigated 49,349 patients with AD and 196,850 controls: long-term (> 5 years) nonsteroidal anti-inflammatory drug use was shown to be protective against Alzheimer disease. These findings were clearest for ibuprofen, but
n3:mentions: n4:8757015

Subject Item: _:vb8570511
rdf:type: n3:Context
rdf:value: These findings were clearest for ibuprofen, but did not appear for other NSAIDs [>>83<<].
n3:mentions: n4:18458226

Subject Item: _:vb8570512
rdf:type: n3:Context
rdf:value: The authors argued that their results could indicate that the disease process was too advanced to be modified, as the goal of the study was slowing the progression of dementia in patients with already established AD [>>8<<]. For another COX-2 inhibitor, celecoxib, no beneficial effect on the occurrence of AD could be demonstrated in an age group over 70 years [84]. Also Wolfson et al. looked retrospectively at a case control population and found no support
n3:mentions: n4:14718699

Subject Item: _:vb8570513
rdf:type: n3:Context
rdf:value: For another COX-2 inhibitor, celecoxib, no beneficial effect on the occurrence of AD could be demonstrated in an age group over 70 years [>>84<<]. Also Wolfson et al. looked retrospectively at a case control population and found no support for a beneficial effect for NSAIDs in the AD subjects [85]. However, this negative result may have been caused by an insufficient period of
n3:mentions: n4:18474729

Subject Item: _:vb8570514
rdf:type: n3:Context
rdf:value: Also Wolfson et al. looked retrospectively at a case control population and found no support for a beneficial effect for NSAIDs in the AD subjects [>>85<<]. However, this negative result may have been caused by an insufficient period of data collection before disease onset.
n3:mentions: n4:11901277

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