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introduction
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neurodegenerative disorder, is the most common cause of dementia among the elderly. It accounts for ∼60-70% of all dementia cases. Prevalence increases with age from ∼1% in the 60–64-year age group, to 24-33% in those aged >85 years.>>1<< The neuropathological hallmarks of AD are the presence in the brain of extracellular senile plaques and intracellular neurofibrillary tangles, along with neuronal loss.
n4:mentions
n2:20136653
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The Aβ peptide itself is derived from the processing of a larger precursor protein known as the amyloid precursor protein (APP).>>2<< The dysfunction of APP metabolism and the consequent accumulation of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals with AD, have been considered crucial for neurodegeneration in the
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of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals with AD, have been considered crucial for neurodegeneration in the disease. This is the so-called “amyloid cascade hypothesis”.>>3<<,4 However, more recently, soluble oligomers of Aβ peptide have been correlated with synaptic loss in the brain of AD subjects.
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of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals with AD, have been considered crucial for neurodegeneration in the disease. This is the so-called “amyloid cascade hypothesis”.3,>>4<< However, more recently, soluble oligomers of Aβ peptide have been correlated with synaptic loss in the brain of AD subjects.
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considered crucial for neurodegeneration in the disease. This is the so-called “amyloid cascade hypothesis”.3,4 However, more recently, soluble oligomers of Aβ peptide have been correlated with synaptic loss in the brain of AD subjects.>>5<<-7 Neurofibrillary tangles contain hyperphosphorylated and aggregated forms of Tau, a microtubule-associated protein that normally promotes the assembly and stability of microtubules in neuronal cells.
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loss in the brain of AD subjects.5-7 Neurofibrillary tangles contain hyperphosphorylated and aggregated forms of Tau, a microtubule-associated protein that normally promotes the assembly and stability of microtubules in neuronal cells.>>2<< Abnormally hyperphosphorylated Tau in AD brain accumulates in neurons into paired helical filaments, which in turn aggregate into neurofibrillary tangles leading to neuronal death.
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and stability of microtubules in neuronal cells.2 Abnormally hyperphosphorylated Tau in AD brain accumulates in neurons into paired helical filaments, which in turn aggregate into neurofibrillary tangles leading to neuronal death.>>8<< Therefore, the neuropathological hallmarks of AD induce progressive neuronal dysfunction and degeneration, resulting in severe brain atrophy and decline of memory and other cognitive functions.
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tangles leading to neuronal death.8 Therefore, the neuropathological hallmarks of AD induce progressive neuronal dysfunction and degeneration, resulting in severe brain atrophy and decline of memory and other cognitive functions.>>2<< Although not a criterion for diagnosis of AD, the deposition of Aβ in the cerebral vasculature, named cerebral amyloid angiopathy (CAA), can be detected in 90% of patients with AD.
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9 However, CAA can occur in the absence of AD pathology and vice versa.>>10<<
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(FAD), an uncommon form that tends to strike sooner, and is related to a genetic predisposition, including mutations in the APP gene on chromosome 21, presenilin 1 (PS1) gene on chromosome 14, and presenilin 2 (PS2) gene on chromosome 1.>>1<< The etiology of AD is unclear and at present there is no effective treatment.
n4:mentions
n2:20136653
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recognizable AD-type pathology. After the discovery of FAD mutations in APP, a number of groups turned their attention to making AD models based on the overexpression of transgenes containing FAD mutations using a variety of promoters.>>11<< This review describes the main transgenic mouse models of AD which have been adopted in AD research, and discusses the insights into AD pathogenesis from studies in transgenic models.
n4:mentions
n2:20101721
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Mutations in APP linked to FAD include Dutch (E693Q),>>10<< London (V717I),12 Indiana (V717F),13 Swedish (K670N/M671L),14 Florida (I716V),15 Iowa (D694N),16 and Arctic (E693G)17 mutations.
n4:mentions
n2:2111584
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),>>12<< Indiana (V717F),13 Swedish (K670N/M671L),14 Florida (I716V),15 Iowa (D694N),16 and Arctic (E693G)17 mutations.
n4:mentions
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),12 Indiana (V717F),>>13<< Swedish (K670N/M671L),14 Florida (I716V),15 Iowa (D694N),16 and Arctic (E693G)17 mutations.
n4:mentions
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),12 Indiana (V717F),13 Swedish (K670N/M671L),>>14<< Florida (I716V),15 Iowa (D694N),16 and Arctic (E693G)17 mutations. To date, more than 160 mutations in PS1 linked to FAD have been discovered (see http:
n4:mentions
n2:1302033
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),12 Indiana (V717F),13 Swedish (K670N/M671L),14 Florida (I716V),>>15<< Iowa (D694N),16 and Arctic (E693G)17 mutations. To date, more than 160 mutations in PS1 linked to FAD have been discovered (see http:
n4:mentions
n2:9328472
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),12 Indiana (V717F),13 Swedish (K670N/M671L),14 Florida (I716V),15 Iowa (D694N),>>16<< and Arctic (E693G)17 mutations. To date, more than 160 mutations in PS1 linked to FAD have been discovered (see http:
n4:mentions
n2:11409420
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Mutations in APP linked to FAD include Dutch (E693Q),10 London (V717I),12 Indiana (V717F),13 Swedish (K670N/M671L),14 Florida (I716V),15 Iowa (D694N),16 and Arctic (E693G)>>17<< mutations. To date, more than 160 mutations in PS1 linked to FAD have been discovered (see http:
n4:mentions
n2:11528419
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and Arctic (E693G)17 mutations. To date, more than 160 mutations in PS1 linked to FAD have been discovered (see http://www.molgen.ua.ac.be/ADMutations). Mutations in a related gene, now called PS2, were soon linked to FAD as well.>>18<< Most of FAD mutations cause aberrant APP processing toward the longer, more amyloidogenic Aβ1-42 species.
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(see http://www.molgen.ua.ac.be/ADMutations). Mutations in a related gene, now called PS2, were soon linked to FAD as well.18 Most of FAD mutations cause aberrant APP processing toward the longer, more amyloidogenic Aβ1-42 species.>>19<< The Aβ is located partially within the ectodomain (N-terminal portion) and partly within the transmembrane domain (C-terminal portion) of APP.
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called amyloidogenic, cleaves APP in the N- and C-terminal portions of the Aβ region, respectively, producing Aβ peptide. γ-Secretase cleaves APP at various adjacent sites to form species of Aβ containing 39 to 43 amino acids.>>20<< Presenilins contribute to the catalytic activity of the γ-secretase complex.1 Processing of APP by α-, β- and γ-secretases is illustrated in Figure 1.
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20 Presenilins contribute to the catalytic activity of the γ-secretase complex.>>1<< Processing of APP by α-, β- and γ-secretases is illustrated in Figure 1.
n4:mentions
n2:20136653
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The Swedish mutation, which is located just outside the N-terminus of the Aβ domain of APP, favors β-secretase cleavage in vitro>>21<< and is associated with an increased level and deposition of Aβ1-42 in AD brain.22 The Dutch and Iowa mutations, which are located in the Aβ domain of APP, accelerate Aβ1-40 fibril formation in vitro.
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The Swedish mutation, which is located just outside the N-terminus of the Aβ domain of APP, favors β-secretase cleavage in vitro21 and is associated with an increased level and deposition of Aβ1-42 in AD brain.>>22<< The Dutch and Iowa mutations, which are located in the Aβ domain of APP, accelerate Aβ1-40 fibril formation in vitro.
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22 The Dutch and Iowa mutations, which are located in the Aβ domain of APP, accelerate Aβ1-40 fibril formation in vitro.>>23<<,24 The Dutch mutation is associated with cerebrovascular Aβ deposition—that is, CAA, resulting in cerebral hemorrhages and dementia in patients with AD,10 whereas the Iowa mutation is associated with severe CAA, widespread neurofibrillary
n4:mentions
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22 The Dutch and Iowa mutations, which are located in the Aβ domain of APP, accelerate Aβ1-40 fibril formation in vitro.23,>>24<< The Dutch mutation is associated with cerebrovascular Aβ deposition—that is, CAA, resulting in cerebral hemorrhages and dementia in patients with AD,10 whereas the Iowa mutation is associated with severe CAA, widespread neurofibrillary
n4:mentions
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23,24 The Dutch mutation is associated with cerebrovascular Aβ deposition—that is, CAA, resulting in cerebral hemorrhages and dementia in patients with AD,>>10<< whereas the Iowa mutation is associated with severe CAA, widespread neurofibrillary tangles, and unusually extensive distribution of Aβ1-40 in plaques in AD brain.
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resulting in cerebral hemorrhages and dementia in patients with AD,10 whereas the Iowa mutation is associated with severe CAA, widespread neurofibrillary tangles, and unusually extensive distribution of Aβ1-40 in plaques in AD brain.>>16<< The Arctic mutation, which is also located inside the Aβ domain, makes APP less available to α-secretase cleavage and increases β-secretase processing of APP thus favoring intracellular Aβ production in vitro.
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in plaques in AD brain.16 The Arctic mutation, which is also located inside the Aβ domain, makes APP less available to α-secretase cleavage and increases β-secretase processing of APP thus favoring intracellular Aβ production in vitro.>>25<<,26 The Arctic mutation is associated with severe CAA in the absence of hemorrhage, abundant parenchymal Aβ deposits, and neurofibrillary tangles in AD brain.
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plaques in AD brain.16 The Arctic mutation, which is also located inside the Aβ domain, makes APP less available to α-secretase cleavage and increases β-secretase processing of APP thus favoring intracellular Aβ production in vitro.25,>>26<< The Arctic mutation is associated with severe CAA in the absence of hemorrhage, abundant parenchymal Aβ deposits, and neurofibrillary tangles in AD brain.
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processing of APP thus favoring intracellular Aβ production in vitro.25,26 The Arctic mutation is associated with severe CAA in the absence of hemorrhage, abundant parenchymal Aβ deposits, and neurofibrillary tangles in AD brain.>>27<< The London mutation, which is located in the transmembrane domain of APP, as well as the PS1 and PS2 mutations alter γ-secretase cleavage and increase the Aβ1-42 level and/or the Aβ1-42/Aβ1-40 ratio in vitro.
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tangles in AD brain.27 The London mutation, which is located in the transmembrane domain of APP, as well as the PS1 and PS2 mutations alter γ-secretase cleavage and increase the Aβ1-42 level and/or the Aβ1-42/Aβ1-40 ratio in vitro.>>28<<-30 The London mutation is associated with extensive parenchymal Aβ deposition and abundant senile plaques and neurofibrillary tangles, as well as moderate CAA in AD brain.
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the Aβ1-42 level and/or the Aβ1-42/Aβ1-40 ratio in vitro.28-30 The London mutation is associated with extensive parenchymal Aβ deposition and abundant senile plaques and neurofibrillary tangles, as well as moderate CAA in AD brain.>>31<<,32 The Indiana mutation, which is also located in the transmembrane domain of APP, is associated with large number of neurofibrillary tangles and senile plaques, as well as mild CAA in AD brain.
n4:mentions
n2:1584463
Subject Item
_:vb11905423
rdf:type
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rdf:value
the Aβ1-42 level and/or the Aβ1-42/Aβ1-40 ratio in vitro.28-30 The London mutation is associated with extensive parenchymal Aβ deposition and abundant senile plaques and neurofibrillary tangles, as well as moderate CAA in AD brain.31,>>32<< The Indiana mutation, which is also located in the transmembrane domain of APP, is associated with large number of neurofibrillary tangles and senile plaques, as well as mild CAA in AD brain.
n4:mentions
n2:8247223
Subject Item
_:vb11905424
rdf:type
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rdf:value
as well as moderate CAA in AD brain.31,32 The Indiana mutation, which is also located in the transmembrane domain of APP, is associated with large number of neurofibrillary tangles and senile plaques, as well as mild CAA in AD brain.>>33<< The Florida mutation, which is also located in the transmembrane domain of APP, affects γ-secretase cleavage causing an increased Aβ1-42 concentration and Aβ1-42/Aβ1-40 ratio in vitro.
n4:mentions
n2:1611485
Subject Item
_:vb11905425
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33 The Florida mutation, which is also located in the transmembrane domain of APP, affects γ-secretase cleavage causing an increased Aβ1-42 concentration and Aβ1-42/Aβ1-40 ratio in vitro.>>15<<,30
n4:mentions
n2:9328472
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_:vb11905426
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rdf:value
33 The Florida mutation, which is also located in the transmembrane domain of APP, affects γ-secretase cleavage causing an increased Aβ1-42 concentration and Aβ1-42/Aβ1-40 ratio in vitro.15,>>30<<
n4:mentions
n2:11487570
Subject Item
_:vb11905427
rdf:type
n4:Context
rdf:value
Games et al>>34<< reported the first transgenic AD model, termed PDAPP mice, which overexpress a human APP transgene containing the Indiana mutation (V717F) under the control of the platelet-derived growth factor-β promoter.
n4:mentions
n2:7845465
Subject Item
_:vb11905428
rdf:type
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rdf:value
The mice developed senile plaques that were primarily composed of Aβ1-42.>>35<< PDAPP mice showed age-related Aβ deposition in cortical and limbic regions that began at 8 months and progressed to cover 20-50% of the neuropil in the cingulate cortex, entorhinal cortex, and hippocampus of 18-month-old animals.
n4:mentions
n2:9037091
Subject Item
_:vb11905429
rdf:type
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rdf:value
neurites and extensive gliosis (reactive astrocytes and activated microglia), however, there was no overt neuronal loss in the entorhinal cortex, hippocampal CA1 field, or cingulate cortex through 18 months of age in PDAPP mice.>>36<< Dystrophic neurites immunoreactive for hyperphosphorylated Tau were observed near Aβ plaques after 14 months of age, although no paired helical filaments and neurofibrillary tangles were identified.
n4:mentions
n2:9278541
Subject Item
_:vb11905430
rdf:type
n4:Context
rdf:value
18 months of age in PDAPP mice.36 Dystrophic neurites immunoreactive for hyperphosphorylated Tau were observed near Aβ plaques after 14 months of age, although no paired helical filaments and neurofibrillary tangles were identified.>>37<< PDAPP mice showed significant and age-dependent synaptic loss, and a rather marked hippocampal atrophy was observed as early as 3 months of age in these mice.
n4:mentions
n2:11305871
Subject Item
_:vb11905431
rdf:type
n4:Context
rdf:value
no paired helical filaments and neurofibrillary tangles were identified.37 PDAPP mice showed significant and age-dependent synaptic loss, and a rather marked hippocampal atrophy was observed as early as 3 months of age in these mice.>>38<< Young PDAPP mice showed deficits in spatial learning and memory, which worsened with increasing age and Aβ burden.
n4:mentions
n2:10783292
Subject Item
_:vb11905432
rdf:type
n4:Context
rdf:value
38 Young PDAPP mice showed deficits in spatial learning and memory, which worsened with increasing age and Aβ burden.>>39<<
n4:mentions
n2:11140684
Subject Item
_:vb11905433
rdf:type
n4:Context
rdf:value
Similarly, Hsiao et al.>>40<< overexpressed in mice a human APP transgene containing the Swedish mutation (K670N/M671L) driven by a hamster prion protein promoter.
n4:mentions
n2:8810256
Subject Item
_:vb11905434
rdf:type
n4:Context
rdf:value
increase of Aβ1-40 and Aβ1-42 levels and Aβ deposition, resulting in senile plaques similar to those found in AD. Aβ plaques were first clearly seen by 11-13 months, eventually becoming widespread in cortical and limbic structures.>>40<< Aβ deposits were associated with prominent gliosis and neuritic dystrophy, without overt neuronal loss in the hippocampal CA1 field or apparent synapse loss in the hippocampal dentate gyrus.
n4:mentions
n2:8810256
Subject Item
_:vb11905435
rdf:type
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rdf:value
40 Aβ deposits were associated with prominent gliosis and neuritic dystrophy, without overt neuronal loss in the hippocampal CA1 field or apparent synapse loss in the hippocampal dentate gyrus.>>41<< Tg2576 mice exhibited deficits in synaptic plasticity in the hippocampal CA1 field and dentate gyrus, decreased dendritic spine density in the dentate gyrus, and impaired spatial memory and contextual fear conditioning months before
n4:mentions
n2:9291938
Subject Item
_:vb11905436
rdf:type
n4:Context
rdf:value
CA1 field and dentate gyrus, decreased dendritic spine density in the dentate gyrus, and impaired spatial memory and contextual fear conditioning months before significant Aβ deposition, which was detectable at 18 months of age.>>42<<,43 A decrease in spine density was detected as early as 4 months of age, and synaptic dysfunction and memory impairment were observed by 5 months.
n4:mentions
n2:10195221
Subject Item
_:vb11905437
rdf:type
n4:Context
rdf:value
CA1 field and dentate gyrus, decreased dendritic spine density in the dentate gyrus, and impaired spatial memory and contextual fear conditioning months before significant Aβ deposition, which was detectable at 18 months of age.42,>>43<< A decrease in spine density was detected as early as 4 months of age, and synaptic dysfunction and memory impairment were observed by 5 months.
n4:mentions
n2:16549764
Subject Item
_:vb11905438
rdf:type
n4:Context
rdf:value
as early as 4 months of age, and synaptic dysfunction and memory impairment were observed by 5 months. Moreover, an increase in the ratio of soluble Aβ1-42/Aβ1-40 was first observed at these early ages—that is, at ∼4-5 months of age.>>43<< Tg2576 mice also showed increased intraneuronal Aβ1-42 accumulation with aging, and this accumulation was associated with abnormal synaptic morphology before Aβ plaque pathology.
n4:mentions
n2:16549764
Subject Item
_:vb11905439
rdf:type
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rdf:value
43 Tg2576 mice also showed increased intraneuronal Aβ1-42 accumulation with aging, and this accumulation was associated with abnormal synaptic morphology before Aβ plaque pathology.>>44<<
n4:mentions
n2:12414533
Subject Item
_:vb11905440
rdf:type
n4:Context
rdf:value
of age. TgCRND8 mice exhibited an excess of brain Aβ1-42 over Aβ1-40, and the high-level production of Aβ1-42 was associated with spatial learning impairment at 6 months of age. Neurofibrillary tangles and neurodegeneration were absent.>>45<< The formation of plaques was concurrent with the appearance of activated microglia and shortly followed by the clustering of activated astrocytes around plaques at 3.5 months of age in TgCRND8 mice.
n4:mentions
n2:11279122
Subject Item
_:vb11905441
rdf:type
n4:Context
rdf:value
45 The formation of plaques was concurrent with the appearance of activated microglia and shortly followed by the clustering of activated astrocytes around plaques at 3.5 months of age in TgCRND8 mice.>>46<<
n4:mentions
n2:15212840
Subject Item
_:vb11905442
rdf:type
n4:Context
rdf:value
in the cerebral cortex and hippocampus that resembled compact Aβ plaques. These mice showed a selective increase in Aβ1-42 in their brains and reduced performance in a spatial memory task before substantial Aβ deposition was apparent.>>47<< The fibrillar Aβ deposits were associated with dystrophic neurites and activated astrocytes and microglia in APP/PS1 mice.
n4:mentions
n2:9427614
Subject Item
_:vb11905443
rdf:type
n4:Context
rdf:value
47 The fibrillar Aβ deposits were associated with dystrophic neurites and activated astrocytes and microglia in APP/PS1 mice.>>48<<
n4:mentions
n2:11822882
Subject Item
_:vb11905444
rdf:type
n4:Context
rdf:value
hippocampus in 24-month-old mice. The Aβ plaques were surrounded by gliosis (activated microglia and astrocytes) and dystrophic neurites that were immunoreactive for hyperphosphorylated Tau despite the lack of neurofibrillary tangles.>>49<< Determination of plaque-associated Aβ1-42 peptides in brain revealed a fivefold increase in APP23 mice at 6 months.
n4:mentions
n2:9371838
Subject Item
_:vb11905445
rdf:type
n4:Context
rdf:value
behavior deficits at 6 months. Spatial memory deficits preceded plaque formation and the increase in plaque-associated Aβ1-42 peptides, but correlated negatively with brain soluble Aβ concentration in 3-month-old APP23 mutants.>>50<< APP23 mice have often been used to study CAA pathogenesis. Significant deposition of Aβ in the cerebral vasculature—that is, CAA was described in aging APP23 mice.
n4:mentions
n2:12542676
Subject Item
_:vb11905446
rdf:type
n4:Context
rdf:value
CAA in these mice was associated with local neuronal loss, synaptic loss, microglial activation, and microhemorrhage.>>51<<,52
n4:mentions
n2:10570203
Subject Item
_:vb11905447
rdf:type
n4:Context
rdf:value
CAA in these mice was associated with local neuronal loss, synaptic loss, microglial activation, and microhemorrhage.51,>>52<<
n4:mentions
n2:11222652
Subject Item
_:vb11905448
rdf:type
n4:Context
rdf:value
Aβ plaque-like deposits in the brain parenchyma starting at 3 months of age with high association with Aβ accumulation in the cerebral microvasculature. Aβ1-40 peptides are largely the predominant species that accumulates in these mice.>>53<< Tg-SwDI mice were impaired in the performance of a spatial learning and memory task at 3, 9, and 12 months of age.
n4:mentions
n2:14985348
Subject Item
_:vb11905449
rdf:type
n4:Context
rdf:value
53 Tg-SwDI mice were impaired in the performance of a spatial learning and memory task at 3, 9, and 12 months of age.>>54<<
n4:mentions
n2:17331655
Subject Item
_:vb11905450
rdf:type
n4:Context
rdf:value
only the Dutch mutation regulated by the Thy1 promoter, showed neuronal overexpression of APP and increased ratio of Aβ1-40/Aβ1-42 in the brain that resulted in extensive vascular Aβ deposition with essentially no parenchymal deposition.>>55<< These researchers also developed a transgenic line that expresses human APP-Dutch mutation crossed with mutant PS1 (G384A), termed APPDutch/PS1 mice.
n4:mentions
n2:15311281
Subject Item
_:vb11905451
rdf:type
n4:Context
rdf:value
with APP-Swedish and APP-Indiana mutations directed by the platelet-derived growth factor-β promoter, termed hAPP-Arc mice, developed prominent parenchymal Aβ plaque deposits with little CAA despite a reduced proportion of Aβ1-42/Aβ1-40.>>56<<
n4:mentions
n2:15502844
Subject Item
_:vb11905452
rdf:type
n4:Context
rdf:value
Tg-ArcSwe mice with both APP-Swedish and APP-Arctic mutations driven by the Thy1 promoter were developed by two independent groups.>>57<<,58 Tg-ArcSwe mice exhibited an age-dependent increase in intraneuronal Aβ accumulation and deficits in spatial memory and contextual fear conditioning, starting at the age of 6 months, before the onset of Aβ plaque formation as well as
n4:mentions
n2:16298242
Subject Item
_:vb11905453
rdf:type
n4:Context
rdf:value
Tg-ArcSwe mice with both APP-Swedish and APP-Arctic mutations driven by the Thy1 promoter were developed by two independent groups.57,>>58<< Tg-ArcSwe mice exhibited an age-dependent increase in intraneuronal Aβ accumulation and deficits in spatial memory and contextual fear conditioning, starting at the age of 6 months, before the onset of Aβ plaque formation as well as CAA.
n4:mentions
n2:16876915
Subject Item
_:vb11905454
rdf:type
n4:Context
rdf:value
Tg-ArcSwe mice exhibited an age-dependent increase in intraneuronal Aβ accumulation and deficits in spatial memory and contextual fear conditioning, starting at the age of 6 months, before the onset of Aβ plaque formation as well as CAA.>>57<<-59 The cognitive impairments correlated inversely with soluble Aβ levels in Tg-ArcSwe mice.
n4:mentions
n2:19215301 n2:16298242 n2:16876915
Subject Item
_:vb11905455
rdf:type
n4:Context
rdf:value
in spatial memory and contextual fear conditioning, starting at the age of 6 months, before the onset of Aβ plaque formation as well as CAA.57-59 The cognitive impairments correlated inversely with soluble Aβ levels in Tg-ArcSwe mice.>>59<< Recently, a mouse model expressing human APP with only the Arctic mutation under the control of the Thy1 promoter, termed APPArc mice, was reported by Rönnbäck et al.
n4:mentions
n2:19215301
Subject Item
_:vb11905456
rdf:type
n4:Context
rdf:value
correlated inversely with soluble Aβ levels in Tg-ArcSwe mice.59 Recently, a mouse model expressing human APP with only the Arctic mutation under the control of the Thy1 promoter, termed APPArc mice, was reported by Rönnbäck et al.>>60<< APPArc mice showed an age-dependent progression of parenchymal and vascular Aβ deposition, starting in the subiculum and spreading to the thalamus, and deficits in hippocampus-dependent spatial learning and memory test.
n4:mentions
n2:19329229
Subject Item
_:vb11905457
rdf:type
n4:Context
rdf:value
In contrast to transgenic models with both the Swedish and Arctic mutations,>>57<<,58 APPArc mice did not show any punctate intraneuronal Aβ immunoreactivity.
n4:mentions
n2:16298242
Subject Item
_:vb11905458
rdf:type
n4:Context
rdf:value
In contrast to transgenic models with both the Swedish and Arctic mutations,57,>>58<< APPArc mice did not show any punctate intraneuronal Aβ immunoreactivity.
n4:mentions
n2:16876915
Subject Item
_:vb11905459
rdf:type
n4:Context
rdf:value
In contrast to transgenic models with both the Swedish and Arctic mutations,57,58 APPArc mice did not show any punctate intraneuronal Aβ immunoreactivity.>>60<<
n4:mentions
n2:19329229
Subject Item
_:vb11905460
rdf:type
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rdf:value
pathology of AD. For example, in PDAPP mice, phosphorylated Tau sites do accumulate within dystrophic neurites in animals of 14 months of age or older, but there are no paired helical filaments and no neurofibrillary tangle-like lesions.>>37<< Other models have been similar in their lack of any neurofibrillary tangle-like pathology, such as TgCRND845 and APP23 mice.
n4:mentions
n2:11305871
Subject Item
_:vb11905461
rdf:type
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rdf:value
37 Other models have been similar in their lack of any neurofibrillary tangle-like pathology, such as TgCRND>>845<< and APP23 mice.
n4:mentions
n2:11279122
Subject Item
_:vb11905462
rdf:type
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rdf:value
37 Other models have been similar in their lack of any neurofibrillary tangle-like pathology, such as TgCRND845 and APP23 mice.>>49<<
n4:mentions
n2:9371838
Subject Item
_:vb11905463
rdf:type
n4:Context
rdf:value
tangle-like lesions and Aβ plaques have been produced by combining FAD mutations with mutant forms of Tau found in a distinct form of dementia known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).>>61<< Lewis et al.62 first crossed Tg2576 mice with a transgenic line known as JNPL3, which expresses P301L mutant Tau associated with FTDP-17, generating a bigenic transgenic model referred to as TAPP mice.
n4:mentions
n2:17659186
Subject Item
_:vb11905464
rdf:type
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rdf:value
lesions and Aβ plaques have been produced by combining FAD mutations with mutant forms of Tau found in a distinct form of dementia known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).61 Lewis et al.>>62<< first crossed Tg2576 mice with a transgenic line known as JNPL3, which expresses P301L mutant Tau associated with FTDP-17, generating a bigenic transgenic model referred to as TAPP mice.
n4:mentions
n2:11520987
Subject Item
_:vb11905465
rdf:type
n4:Context
rdf:value
Later, Oddo et al.>>63<< generated a triple transgenic model of AD, termed 3xTg-AD mice, which expressed human APP-Swedish (K670N/M671L) and FTDP-17 Tau (P301L) mutations from exogenous transgenes regulated by the Thy1 promoter combined with a PS1 mutation
n4:mentions
n2:12895417
Subject Item
_:vb11905466
rdf:type
n4:Context
rdf:value
first became apparent in 6-month-old mice in the frontal cortex and were readily evident by 12 months in other cortical regions and in the hippocampus. Aβ plaques preceded Tau pathology, which was not evident until about 1 year of age.>>63<<,64 Tau was conformationally altered and hyperphosphorylated at multiple residues in the brain of 3xTg-AD mice in an age-related manner.
n4:mentions
n2:12895417
Subject Item
_:vb11905467
rdf:type
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rdf:value
became apparent in 6-month-old mice in the frontal cortex and were readily evident by 12 months in other cortical regions and in the hippocampus. Aβ plaques preceded Tau pathology, which was not evident until about 1 year of age.63,>>64<< Tau was conformationally altered and hyperphosphorylated at multiple residues in the brain of 3xTg-AD mice in an age-related manner.
n4:mentions
n2:15748844
Subject Item
_:vb11905468
rdf:type
n4:Context
rdf:value
Functionally, 3xTg-AD mice developed age-dependent synaptic plasticity deficits, but before Aβ plaque and neurofibrillary tangle pathologies; synaptic dysfunction correlated with the accumulation of intraneuronal Aβ1-42.>>63<< In addition, these mice manifested earliest retention impairment in spatial memory at 4 months of age that correlated with the accumulation of intraneuronal Aβ1-42.
n4:mentions
n2:12895417
Subject Item
_:vb11905469
rdf:type
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rdf:value
At 6 months of age, 3xTg-AD mice showed retention deficits in spatial memory and contextual fear conditioning tasks.>>64<<
n4:mentions
n2:15748844
Subject Item
_:vb11905470
rdf:type
n4:Context
rdf:value
Another problem with the AD transgenic mouse models has been the general difficulty of producing neuronal loss. For example, neither PDAPP nor Tg2576 mice, despite having extensive Aβ deposition, exhibit significant neuronal loss.>>36<<,41 APP23 mice show only modest losses of pyramidal cells in hippocampal CA1 field (about 15%), losses that are far less than those observed in AD.
n4:mentions
n2:9278541
Subject Item
_:vb11905471
rdf:type
n4:Context
rdf:value
Another problem with the AD transgenic mouse models has been the general difficulty of producing neuronal loss. For example, neither PDAPP nor Tg2576 mice, despite having extensive Aβ deposition, exhibit significant neuronal loss.36,>>41<< APP23 mice show only modest losses of pyramidal cells in hippocampal CA1 field (about 15%), losses that are far less than those observed in AD.
n4:mentions
n2:9291938
Subject Item
_:vb11905472
rdf:type
n4:Context
rdf:value
No quantitative evidence of neuronal loss was observed in the neocortex as a whole.>>65<<
n4:mentions
n2:10192220
Subject Item
_:vb11905473
rdf:type
n4:Context
rdf:value
More substantial neuronal loss has been reported in mice expressing multiple APP and PS1 mutations.>>66<<-68 One model showing massive neuronal loss is APPSL/PS1 mice, which express human APP with the Swedish and London (V717I) mutations driven by the Thy1 promoter and human PS1 with the M146L mutation under the control of the
n4:mentions
n2:15466394 n2:17021169 n2:12146796
Subject Item
_:vb11905474
rdf:type
n4:Context
rdf:value
Aβ1-40 and Aβ1-42 stainings preceded Aβ plaque deposition, which started at 3 months of age. Aβ was observed in the somatodendritic and axonal compartments of neurons in the subiculum, hippocampal CA1 field, as well as in cortical areas.>>66<< The Aβ1-42/Aβ1-40 ratio was increased in APPSL/PS1 mice.69 A substantial loss (about 30%) of pyramidal neurons in the hippocampal CA1-3 fields was detected in 17-month-old APPSL/PS1 mice.
n4:mentions
n2:12146796
Subject Item
_:vb11905475
rdf:type
n4:Context
rdf:value
which started at 3 months of age. Aβ was observed in the somatodendritic and axonal compartments of neurons in the subiculum, hippocampal CA1 field, as well as in cortical areas.66 The Aβ1-42/Aβ1-40 ratio was increased in APPSL/PS1 mice.>>69<< A substantial loss (about 30%) of pyramidal neurons in the hippocampal CA1-3 fields was detected in 17-month-old APPSL/PS1 mice.
n4:mentions
n2:15972962
Subject Item
_:vb11905476
rdf:type
n4:Context
rdf:value
was detected in 17-month-old APPSL/PS1 mice. The loss of neurons was observed at sites of Aβ aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from Aβ plaques.>>70<< Furthermore, APPSL/PS1 mice displayed severe age-related synaptic loss within hippocampal dentate gyrus and CA1-3 fields at 17 months of age, even in regions free of extracellular Aβ deposits.
n4:mentions
n2:15039236
Subject Item
_:vb11905477
rdf:type
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rdf:value
70 Furthermore, APPSL/PS1 mice displayed severe age-related synaptic loss within hippocampal dentate gyrus and CA1-3 fields at 17 months of age, even in regions free of extracellular Aβ deposits.>>69<<
n4:mentions
n2:15972962
Subject Item
_:vb11905478
rdf:type
n4:Context
rdf:value
and numerous Aβ deposits were found within the hippocampal, cortical, and thalamic areas. Aβ1-42 was the predominant (85%) Aβ isovariant produced in APP/PS1KI mice, and Aβ1-42 oligomers were highly abundant in the APP/PS1KI brain.>>67<< Further pathological features starting at the age of 6 months included severe axonal degeneration, as well as reduced ability to perform working memory and motor tasks.
n4:mentions
n2:15466394
Subject Item
_:vb11905479
rdf:type
n4:Context
rdf:value
and Aβ1-42 oligomers were highly abundant in the APP/PS1KI brain.67 Further pathological features starting at the age of 6 months included severe axonal degeneration, as well as reduced ability to perform working memory and motor tasks.>>71<<,72 At this time point also synaptic dysfunction and loss became evident in APP/PS1KI brain.
n4:mentions
n2:16963164
Subject Item
_:vb11905480
rdf:type
n4:Context
rdf:value
Aβ1-42 oligomers were highly abundant in the APP/PS1KI brain.67 Further pathological features starting at the age of 6 months included severe axonal degeneration, as well as reduced ability to perform working memory and motor tasks.71,>>72<< At this time point also synaptic dysfunction and loss became evident in APP/PS1KI brain.
n4:mentions
n2:17215062
Subject Item
_:vb11905481
rdf:type
n4:Context
rdf:value
brain. In addition, at 6 months of age, a loss of 33% of hippocampal CA1 pyramidal neurons was demonstrated, together with a decreased volume of the CA1 pyramidal cell layer of 30%, and an atrophy of the entire hippocampus of 18%.>>73<< Analysis of the frontal cortex revealed an early loss of cortical neurons starting at the age of 6 months which correlated with the transient intraneuronal Aβ accumulation in contrast to extracellular Aβ plaque pathology.
n4:mentions
n2:19387667
Subject Item
_:vb11905482
rdf:type
n4:Context
rdf:value
73 Analysis of the frontal cortex revealed an early loss of cortical neurons starting at the age of 6 months which correlated with the transient intraneuronal Aβ accumulation in contrast to extracellular Aβ plaque pathology.>>74<< At 10 months of age, an extensive neuronal loss (>50%) was present in the pyramidal cell layer of hippocampal CA1/2 fields that correlated with strong accumulation of intraneuronal Aβ but not with extracellular Aβ deposits in APP/PS1KI
n4:mentions
n2:18974993
Subject Item
_:vb11905483
rdf:type
n4:Context
rdf:value
A very significant astrogliosis developed in the area of strong intraneuronal Aβ accumulation and neuronal loss.>>67<<
n4:mentions
n2:15466394
Subject Item
_:vb11905484
rdf:type
n4:Context
rdf:value
Aβ deposits at 2 months. Synaptic loss started already at 4 months of age and was significant from 9 months in 5xFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum were visibly reduced in number at 9 months of age.>>68<< 5xFAD mice developed deficits in spatial memory tasks and also exhibited impairments in trace and contextual fear conditioning tests at 4-6 months of age.
n4:mentions
n2:17021169
Subject Item
_:vb11905485
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rdf:value
68 5xFAD mice developed deficits in spatial memory tasks and also exhibited impairments in trace and contextual fear conditioning tests at 4-6 months of age.>>68<<,75
n4:mentions
n2:17021169
Subject Item
_:vb11905486
rdf:type
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rdf:value
68 5xFAD mice developed deficits in spatial memory tasks and also exhibited impairments in trace and contextual fear conditioning tests at 4-6 months of age.68,>>75<<
n4:mentions
n2:17258906
Subject Item
_:vb11905487
rdf:type
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models fully replicates the human disease, they have suggested new insights into the pathophysiology of Aβ toxicity, particularly with respect to the effects of different Aβ species and the possible pathogenic role of Aβ oligomers.>>11<<
n4:mentions
n2:20101721
Subject Item
_:vb11905488
rdf:type
n4:Context
rdf:value
In the 1980s it was debated whether Aβ deposits, and in particular CAA at the cerebral vessel walls, had a central nervous system or a peripheral source.>>11<< Studies in APP23 mice, which developed a similar degree of both Aβ plaques and CAA, provided the first evidence that a neuronal source of APP/Aβ is sufficient to induce cerebrovascular Aβ and associated neurodegeneration.
n4:mentions
n2:20101721
Subject Item
_:vb11905489
rdf:type
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rdf:value
11 Studies in APP23 mice, which developed a similar degree of both Aβ plaques and CAA, provided the first evidence that a neuronal source of APP/Aβ is sufficient to induce cerebrovascular Aβ and associated neurodegeneration.>>51<< Accordingly, studies in transgenic mice with almost exclusive neuronal central nervous system expression of APP, like APPDutch mice, which develop almost only CAA, strongly suggest that neuronal Aβ produced in the brain generates
n4:mentions
n2:10570203
Subject Item
_:vb11905490
rdf:type
n4:Context
rdf:value
be needed as a seed for Aβ deposition in either compartment (parenchyma and vasculature), studies in APPDutch and APPDutch/PS1 mice suggest that Aβ1-40 promotes vascular deposition, whereas Aβ1-42 shifts deposition toward parenchymal Aβ.>>55<< Moreover, studies in hAPP-Arc mice, with APP-Arctic mutation (E693G) combined with APP-Swedish and APP-Indiana mutations, suggest that some property of the APP E693G mutation, besides its effect on the Aβ1-40/Aβ1-42 ratio, may also
n4:mentions
n2:15311281
Subject Item
_:vb11905491
rdf:type
n4:Context
rdf:value
(E693G) combined with APP-Swedish and APP-Indiana mutations, suggest that some property of the APP E693G mutation, besides its effect on the Aβ1-40/Aβ1-42 ratio, may also influence parenchymal deposition versus vascular deposition.>>56<< Therefore, the existing AD transgenic mouse models have shown considerable utility in deciphering the pathobiology of CAA.
n4:mentions
n2:15502844
Subject Item
_:vb11905492
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,>>35<<,36 Tg2576,40,41 TgCRND8,45 and APP2365 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:9037091
Subject Item
_:vb11905493
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,35,>>36<< Tg2576,40,41 TgCRND8,45 and APP2365 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:9278541
Subject Item
_:vb11905494
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,35,36 Tg2576,>>40<<,41 TgCRND8,45 and APP2365 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:8810256
Subject Item
_:vb11905495
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,35,36 Tg2576,40,>>41<< TgCRND8,45 and APP2365 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:9291938
Subject Item
_:vb11905496
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,35,36 Tg2576,40,41 TgCRND8,>>45<< and APP2365 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:11279122
Subject Item
_:vb11905497
rdf:type
n4:Context
rdf:value
Analyses of the brain of APP transgenic mouse models in which large amounts of Aβ have accumulated in plaques but no neurodegeneration has developed, such as PDAPP,35,36 Tg2576,40,41 TgCRND8,45 and APP>>2365<< mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.
n4:mentions
n2:10192220
Subject Item
_:vb11905498
rdf:type
n4:Context
rdf:value
This hypothesis supports the idea that increased Aβ production and extracellular accumulation in plaques leads to neurotoxicity, resulting in widespread neuronal loss and dementia.>>76<< Some reasons for this have been discussed.
n4:mentions
n2:12130773
Subject Item
_:vb11905499
rdf:type
n4:Context
rdf:value
is sparse in APP mouse models because murine neurons might be devoid of the downstream pathways necessary for Aβ to induce toxicity, such as the processes leading to Tau aggregation and neurofibrillary tangle formation in AD brain.>>11<< Interestingly, subsequent to the original amyloid hypothesis, it became clear that Aβ plaque counts correlate relatively poorly with the level of cognitive decline in AD and that the number of neurofibrillary tangles correlates more
n4:mentions
n2:20101721
Subject Item
_:vb11905500
rdf:type
n4:Context
rdf:value
original amyloid hypothesis, it became clear that Aβ plaque counts correlate relatively poorly with the level of cognitive decline in AD and that the number of neurofibrillary tangles correlates more strongly with the degree of dementia.>>77<< Perhaps only certain species of Aβ (Aβ1-40, Aβ1-42, or truncated Aβ) are neurotoxic, and by using mutations linked to familial AD we poorly replicate the processes of Aβ production and aggregation in sporadic AD brain.
n4:mentions
n2:1307688
Subject Item
_:vb11905501
rdf:type
n4:Context
rdf:value
of dementia.77 Perhaps only certain species of Aβ (Aβ1-40, Aβ1-42, or truncated Aβ) are neurotoxic, and by using mutations linked to familial AD we poorly replicate the processes of Aβ production and aggregation in sporadic AD brain.>>11<< Curiously, truncated Aβ peptides were demonstrated in AD brain more than 10 years ago,78,79 but the observations were partially ignored.
n4:mentions
n2:20101721
Subject Item
_:vb11905502
rdf:type
n4:Context
rdf:value
11 Curiously, truncated Aβ peptides were demonstrated in AD brain more than 10 years ago,>>78<<,79 but the observations were partially ignored.
n4:mentions
n2:8428986
Subject Item
_:vb11905503
rdf:type
n4:Context
rdf:value
11 Curiously, truncated Aβ peptides were demonstrated in AD brain more than 10 years ago,78,>>79<< but the observations were partially ignored.
n4:mentions
n2:7857653
Subject Item
_:vb11905504
rdf:type
n4:Context
rdf:value
partially ignored. Today it is well established that only a fraction of Aβ in postmortem AD brain is full-length Aβ1-40 or Aβ1-42; N-terminally truncated variants of Aβ (Aβ3-42 and Aβ11-42) are prevalent in senile plaques of AD brain.>>80<<,81 Unlike the classical amyloid cascade hypothesis, it was subsequently shown that soluble oligomers of Aβ1-42 and not plaque-associated Aβ correlate best with cognitive dysfunction in AD.
n4:mentions
n2:9224700
Subject Item
_:vb11905505
rdf:type
n4:Context
rdf:value
partially ignored. Today it is well established that only a fraction of Aβ in postmortem AD brain is full-length Aβ1-40 or Aβ1-42; N-terminally truncated variants of Aβ (Aβ3-42 and Aβ11-42) are prevalent in senile plaques of AD brain.80,>>81<< Unlike the classical amyloid cascade hypothesis, it was subsequently shown that soluble oligomers of Aβ1-42 and not plaque-associated Aβ correlate best with cognitive dysfunction in AD.
n4:mentions
n2:11162251
Subject Item
_:vb11905506
rdf:type
n4:Context
rdf:value
80,81 Unlike the classical amyloid cascade hypothesis, it was subsequently shown that soluble oligomers of Aβ1-42 and not plaque-associated Aβ correlate best with cognitive dysfunction in AD.>>6<<,82
n4:mentions
n2:10589538
Subject Item
_:vb11905507
rdf:type
n4:Context
rdf:value
80,81 Unlike the classical amyloid cascade hypothesis, it was subsequently shown that soluble oligomers of Aβ1-42 and not plaque-associated Aβ correlate best with cognitive dysfunction in AD.6,>>82<<
n4:mentions
n2:10735393
Subject Item
_:vb11905508
rdf:type
n4:Context
rdf:value
is now a great interest in identifying which Aβ species (Aβ1-40, Aβ1-42, or truncated Aβ) and form (oligomers or deposits) would be responsible for neurotoxicity, and in understanding the relationship between Aβ and Tau pathologies.>>11<< APP transgenic mice have provided strong evidence for the toxicity of soluble Aβ oligomers in vivo by showing that many pathological and functional changes in mice occur before the appearance of Aβ plaque pathology.
n4:mentions
n2:20101721
Subject Item
_:vb11905509
rdf:type
n4:Context
rdf:value
of Aβ plaque pathology. For example, studies in PDAPP mice demonstrated that loss of volume in the hippocampus, predominantly localized to the dentate gyrus, was present in 100-day-old mice well before Aβ deposition in plaques.>>83<< In addition, loss in total dendritic length was evident in the dentate gyrus of 90-day-old PDAPP mice well before Aβ accumulation occurs.
n4:mentions
n2:12552120
Subject Item
_:vb11905510
rdf:type
n4:Context
rdf:value
83 In addition, loss in total dendritic length was evident in the dentate gyrus of 90-day-old PDAPP mice well before Aβ accumulation occurs.>>84<< Tg2576 mice exhibited increased ratio of soluble Aβ1-42/Aβ1-40, deficits in synaptic plasticity in the hippocampal CA1 field and dentate gyrus, loss of dendritic spines in the dentate gyrus, and impaired spatial and contextual memory
n4:mentions
n2:15118092
Subject Item
_:vb11905511
rdf:type
n4:Context
rdf:value
of soluble Aβ1-42/Aβ1-40, deficits in synaptic plasticity in the hippocampal CA1 field and dentate gyrus, loss of dendritic spines in the dentate gyrus, and impaired spatial and contextual memory months before significant Aβ deposition.>>42<<,43 In APP23 mice, spatial memory deficits preceded plaque formation and the increase in plaque-associated Aβ1-42 peptides, but correlated negatively with soluble Aβ concentration.
n4:mentions
n2:10195221
Subject Item
_:vb11905512
rdf:type
n4:Context
rdf:value
soluble Aβ1-42/Aβ1-40, deficits in synaptic plasticity in the hippocampal CA1 field and dentate gyrus, loss of dendritic spines in the dentate gyrus, and impaired spatial and contextual memory months before significant Aβ deposition.42,>>43<< In APP23 mice, spatial memory deficits preceded plaque formation and the increase in plaque-associated Aβ1-42 peptides, but correlated negatively with soluble Aβ concentration.
n4:mentions
n2:16549764
Subject Item
_:vb11905513
rdf:type
n4:Context
rdf:value
memory months before significant Aβ deposition.42,43 In APP23 mice, spatial memory deficits preceded plaque formation and the increase in plaque-associated Aβ1-42 peptides, but correlated negatively with soluble Aβ concentration.>>50<< Tg-ArcSwe mice exhibited robust deficits in spatial memory and contextual fear conditioning before the onset of Aβ deposition,57-59 and the cognitive impairments correlated inversely with soluble Aβ levels.
n4:mentions
n2:12542676
Subject Item
_:vb11905514
rdf:type
n4:Context
rdf:value
50 Tg-ArcSwe mice exhibited robust deficits in spatial memory and contextual fear conditioning before the onset of Aβ deposition,>>57<<-59 and the cognitive impairments correlated inversely with soluble Aβ levels.
n4:mentions
n2:16298242 n2:19215301 n2:16876915
Subject Item
_:vb11905515
rdf:type
n4:Context
rdf:value
50 Tg-ArcSwe mice exhibited robust deficits in spatial memory and contextual fear conditioning before the onset of Aβ deposition,57-59 and the cognitive impairments correlated inversely with soluble Aβ levels.>>59<< 3xTg-AD mice developed age-dependent synaptic plasticity deficits and spatial memory impairment before Aβ plaque and neurofibrillary tangle pathologies but instead in correlation with soluble Aβ1-42.63,64 Finally, APP/PS1 mice, which
n4:mentions
n2:19215301
Subject Item
_:vb11905516
rdf:type
n4:Context
rdf:value
59 3xTg-AD mice developed age-dependent synaptic plasticity deficits and spatial memory impairment before Aβ plaque and neurofibrillary tangle pathologies but instead in correlation with soluble Aβ1-42.>>63<<,64 Finally, APP/PS1 mice, which exhibit large numbers of compact Aβ plaques in the cerebral cortex and hippocampus, showed a selective increase in Aβ1-42 in their brains and reduced performance in a spatial memory task in the period
n4:mentions
n2:12895417
Subject Item
_:vb11905517
rdf:type
n4:Context
rdf:value
59 3xTg-AD mice developed age-dependent synaptic plasticity deficits and spatial memory impairment before Aβ plaque and neurofibrillary tangle pathologies but instead in correlation with soluble Aβ1-42.63,>>64<< Finally, APP/PS1 mice, which exhibit large numbers of compact Aβ plaques in the cerebral cortex and hippocampus, showed a selective increase in Aβ1-42 in their brains and reduced performance in a spatial memory task in the period
n4:mentions
n2:15748844
Subject Item
_:vb11905518
rdf:type
n4:Context
rdf:value
which exhibit large numbers of compact Aβ plaques in the cerebral cortex and hippocampus, showed a selective increase in Aβ1-42 in their brains and reduced performance in a spatial memory task in the period preceding overt Aβ deposition.>>47<< These studies are consistent with the more critical role of Aβ1-42 in the pathogenesis of AD and suggest a neurotoxic effect of soluble forms of Aβ.
n4:mentions
n2:9427614
Subject Item
_:vb11905519
rdf:type
n4:Context
rdf:value
Since the discovery that truncated Aβ3-42 represents a major species in senile plaques of AD brain,>>80<<,81 this peptide has received considerable attention. In comparison with Aβ1-42, Aβ3-42 has stronger aggregation propensity and increased toxicity in vitro.
n4:mentions
n2:9224700
Subject Item
_:vb11905520
rdf:type
n4:Context
rdf:value
Since the discovery that truncated Aβ3-42 represents a major species in senile plaques of AD brain,80,>>81<< this peptide has received considerable attention. In comparison with Aβ1-42, Aβ3-42 has stronger aggregation propensity and increased toxicity in vitro.
n4:mentions
n2:11162251
Subject Item
_:vb11905521
rdf:type
n4:Context
rdf:value
In comparison with Aβ1-42, Aβ3-42 has stronger aggregation propensity and increased toxicity in vitro.>>85<<-87 Recently, a new transgenic mouse model (TBA2) was generated,88 which expressed only truncated Aβ3-42 in neurons without any of the other Aβ peptides, and it was demonstrated for the first time that this peptide is neurotoxic in vivo,
n4:mentions
n2:10451383 n2:12354296 n2:17029395
Subject Item
_:vb11905522
rdf:type
n4:Context
rdf:value
In comparison with Aβ1-42, Aβ3-42 has stronger aggregation propensity and increased toxicity in vitro.85-87 Recently, a new transgenic mouse model (TBA2) was generated,>>88<< which expressed only truncated Aβ3-42 in neurons without any of the other Aβ peptides, and it was demonstrated for the first time that this peptide is neurotoxic in vivo, inducing neuronal loss and concomitant neurological deficits
n4:mentions
n2:19547991
Subject Item
_:vb11905523
rdf:type
n4:Context
rdf:value
extracellularly, whereas recent evidence points to toxic effects of Aβ in intracellular compartments. First reports showing that Aβ is initially deposited in neurons before occurring in the extracellular space date back roughly 20 years.>>89<<,90 More recently, it has been shown that neurons in AD-vulnerable regions accumulate Aβ1-42 and it has been further suggested that this accumulation precedes extracellular Aβ deposition and neurofibrillary tangle formation.
n4:mentions
n2:4065091
Subject Item
_:vb11905524
rdf:type
n4:Context
rdf:value
whereas recent evidence points to toxic effects of Aβ in intracellular compartments. First reports showing that Aβ is initially deposited in neurons before occurring in the extracellular space date back roughly 20 years.89,>>90<< More recently, it has been shown that neurons in AD-vulnerable regions accumulate Aβ1-42 and it has been further suggested that this accumulation precedes extracellular Aβ deposition and neurofibrillary tangle formation.
n4:mentions
n2:2649895
Subject Item
_:vb11905525
rdf:type
n4:Context
rdf:value
20 years.89,90 More recently, it has been shown that neurons in AD-vulnerable regions accumulate Aβ1-42 and it has been further suggested that this accumulation precedes extracellular Aβ deposition and neurofibrillary tangle formation.>>91<< Consecutively, a variety of reports has been published demonstrating Aβ in neurons of AD brain.
n4:mentions
n2:10623648
Subject Item
_:vb11905526
rdf:type
n4:Context
rdf:value
Aβ1-42 and it has been further suggested that this accumulation precedes extracellular Aβ deposition and neurofibrillary tangle formation.91 Consecutively, a variety of reports has been published demonstrating Aβ in neurons of AD brain.>>92<<-95 Curiously, soluble Aβ oligomers, which have been suggested as the most toxic species, are formed, preferentially, intracellularly within neuronal processes and synapses rather than extracellularly.
n4:mentions
n2:11207825 n2:10615894 n2:15168346 n2:12429373
Subject Item
_:vb11905527
rdf:type
n4:Context
rdf:value
Aβ in neurons of AD brain.92-95 Curiously, soluble Aβ oligomers, which have been suggested as the most toxic species, are formed, preferentially, intracellularly within neuronal processes and synapses rather than extracellularly.>>96<<,97 In all transgenic mouse models in which marked neuronal loss has been so far reported, this was preceded by considerable amounts of intraneuronal Aβ peptides.
n4:mentions
n2:10978169
Subject Item
_:vb11905528
rdf:type
n4:Context
rdf:value
Aβ in neurons of AD brain.92-95 Curiously, soluble Aβ oligomers, which have been suggested as the most toxic species, are formed, preferentially, intracellularly within neuronal processes and synapses rather than extracellularly.96,>>97<< In all transgenic mouse models in which marked neuronal loss has been so far reported, this was preceded by considerable amounts of intraneuronal Aβ peptides.
n4:mentions
n2:15071107
Subject Item
_:vb11905529
rdf:type
n4:Context
rdf:value
96,97 In all transgenic mouse models in which marked neuronal loss has been so far reported, this was preceded by considerable amounts of intraneuronal Aβ peptides.>>98<< For example, in APP/PS1KI mice, which developed severe learning deficits correlating with CA1 field neuronal loss and hippocampal atrophy, increased intraneuronal Aβ1-42 and not plaque-associated Aβ coincided well with neuronal loss; the
n4:mentions
n2:20552046
Subject Item
_:vb11905530
rdf:type
n4:Context
rdf:value
atrophy, increased intraneuronal Aβ1-42 and not plaque-associated Aβ coincided well with neuronal loss; the intraneuronal N-truncated Aβ3-42 species was also increased, however, the dominant species was Aβ1-42 in the APP/PS1KI model.>>67<<,73 In agreement with this study, investigations in TBA2 mice showed for the first time that intraneuronal Aβ3-42 accumulation is sufficient for triggering neuronal death and inducing an associated neurological phenotype.
n4:mentions
n2:15466394
Subject Item
_:vb11905531
rdf:type
n4:Context
rdf:value
atrophy, increased intraneuronal Aβ1-42 and not plaque-associated Aβ coincided well with neuronal loss; the intraneuronal N-truncated Aβ3-42 species was also increased, however, the dominant species was Aβ1-42 in the APP/PS1KI model.67,>>73<< In agreement with this study, investigations in TBA2 mice showed for the first time that intraneuronal Aβ3-42 accumulation is sufficient for triggering neuronal death and inducing an associated neurological phenotype.
n4:mentions
n2:19387667
Subject Item
_:vb11905532
rdf:type
n4:Context
rdf:value
an associated neurological phenotype. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrated that intraneuronal Aβ3-42 is neurotoxic in vivo.>>88<< Intraneuronal Aβ1-42 accumulation has also been reported in several transgenic mouse models with no overt neuronal loss, including Tg2576,44 3xTg-AD,63 and 5xFAD.
n4:mentions
n2:19547991
Subject Item
_:vb11905533
rdf:type
n4:Context
rdf:value
88 Intraneuronal Aβ1-42 accumulation has also been reported in several transgenic mouse models with no overt neuronal loss, including Tg2576,>>44<< 3xTg-AD,63 and 5xFAD.
n4:mentions
n2:12414533
Subject Item
_:vb11905534
rdf:type
n4:Context
rdf:value
88 Intraneuronal Aβ1-42 accumulation has also been reported in several transgenic mouse models with no overt neuronal loss, including Tg2576,44 3xTg-AD,>>63<< and 5xFAD.
n4:mentions
n2:12895417
Subject Item
_:vb11905535
rdf:type
n4:Context
rdf:value
it clearly demonstrated that intraneuronal Aβ3-42 is neurotoxic in vivo.88 Intraneuronal Aβ1-42 accumulation has also been reported in several transgenic mouse models with no overt neuronal loss, including Tg2576,44 3xTg-AD,63 and 5xFAD.>>68<< These studies indicate that intraneuronal soluble Aβ is a pathological feature of AD that has long been neglected and is turning out to be the key factor leading to neuronal loss in the disease before the extracellular Aβ deposition.
n4:mentions
n2:17021169
Subject Item
_:vb11905536
rdf:type
n4:Context
rdf:value
Loss of neuronal synaptic density and synapse number represents another invariant feature of AD that appears to precede overt neuronal degeneration.>>99<<,100 Notably, it has been shown that the loss of synaptic terminals correlates better with cognitive decline than plaque and tangle load or neuronal loss, leading to the concept that losing synapses is one of the key events leading to
n4:mentions
n2:2360787
Subject Item
_:vb11905537
rdf:type
n4:Context
rdf:value
Loss of neuronal synaptic density and synapse number represents another invariant feature of AD that appears to precede overt neuronal degeneration.99,>>100<< Notably, it has been shown that the loss of synaptic terminals correlates better with cognitive decline than plaque and tangle load or neuronal loss, leading to the concept that losing synapses is one of the key events leading to
n4:mentions
n2:2002880
Subject Item
_:vb11905538
rdf:type
n4:Context
rdf:value
shown that the loss of synaptic terminals correlates better with cognitive decline than plaque and tangle load or neuronal loss, leading to the concept that losing synapses is one of the key events leading to cognitive dysfunction in AD.>>37<<,101-104 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers not only early neuronal loss but also synaptic deficits.
n4:mentions
n2:11305871
Subject Item
_:vb11905539
rdf:type
n4:Context
rdf:value
that the loss of synaptic terminals correlates better with cognitive decline than plaque and tangle load or neuronal loss, leading to the concept that losing synapses is one of the key events leading to cognitive dysfunction in AD.37,>>101<<-104 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers not only early neuronal loss but also synaptic deficits.
n4:mentions
n2:9258263 n2:2203107 n2:7566338 n2:1789684
Subject Item
_:vb11905540
rdf:type
n4:Context
rdf:value
For example, Tg2576 mice showed increased intraneuronal Aβ1-42 accumulation with aging, and this accumulation was associated with abnormal synaptic morphology before Aβ plaque pathology.>>44<< 3xTg-AD mice developed age-dependent synaptic plasticity deficits, but before Aβ plaque and neurofibrillary tangle pathologies; synaptic dysfunction correlated with the accumulation of intraneuronal Aβ1-42.63 Intraneuronal Aβ1-42
n4:mentions
n2:12414533
Subject Item
_:vb11905541
rdf:type
n4:Context
rdf:value
44 3xTg-AD mice developed age-dependent synaptic plasticity deficits, but before Aβ plaque and neurofibrillary tangle pathologies; synaptic dysfunction correlated with the accumulation of intraneuronal Aβ1-42.>>63<< Intraneuronal Aβ1-42 accumulated in 5xFAD brain starting at 1.5 months of age, just before the first appearance of Aβ deposits at 2 months.
n4:mentions
n2:12895417
Subject Item
_:vb11905542
rdf:type
n4:Context
rdf:value
Synaptic loss started already at 4 months of age and was significant from 9 months in 5xFAD brain, whereas local neuronal loss first became apparent at 9 months of age.>>68<< The development of the APPSL/PS1 mice, which exhibit intraneuronal Aβ1-42 accumulation, offered for the first time the possibility to address the question of whether alterations in synaptic integrity precede neuronal loss in a transgenic
n4:mentions
n2:17021169
Subject Item
_:vb11905543
rdf:type
n4:Context
rdf:value
model of AD, and the data indicated that loss of neurons was of limited impact on age-related synaptic loss and that at least part of synaptic loss seen in regions free of Aβ deposits was due to elevated levels of soluble Aβ oligomers.>>69<<
n4:mentions
n2:15972962
Subject Item
_:vb11905544
rdf:type
n4:Context
rdf:value
regions, most notably the amygdala, in comparison with transgenic JNPL3 animals (expressing singly P301L mutant Tau), suggesting that the formation of Tau inclusions might be influenced by increasing the level of APP or Aβ peptides.>>62<< Additionally, intracerebral injections of anti-Aβ antibodies into the hippocampus of 3xTg-AD mice not only reduced Aβ accumulation but also resulted in clearance of early-stage, but not late-stage, hyperphosphorylated Tau aggregates.
n4:mentions
n2:11520987
Subject Item
_:vb11905545
rdf:type
n4:Context
rdf:value
Thus, Aβ was cleared first, followed by the clearance of Tau localized in the somatodendritic compartment. Conversely, by 30 days after injection, Aβ deposits reemerged, although the Tau pathology was not apparent at this time point.>>105<< These studies thus show that modulating Aβ affects Tau pathology and suggest that Tau pathology may be downstream of Aβ generation.
n4:mentions
n2:15294141
Subject Item
_:vb11905546
rdf:type
n5:Section
dc:title
conclusion
n5:contains
_:vb11905548 _:vb11905549 _:vb11905550 _:vb11905551 _:vb11905547 _:vb11905564 _:vb11905565 _:vb11905566 _:vb11905567 _:vb11905560 _:vb11905561 _:vb11905562 _:vb11905563 _:vb11905556 _:vb11905557 _:vb11905558 _:vb11905559 _:vb11905552 _:vb11905553 _:vb11905554 _:vb11905555 _:vb11905568
Subject Item
_:vb11905547
rdf:type
n4:Context
rdf:value
To study AD, a variety of transgenic mouse models has been generated through the overexpression of the APP and/or the presenilins harboring one or several mutations found in familial AD.>>34<<,40,45,49,53, Although none of the AD transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and
n4:mentions
n2:7845465
Subject Item
_:vb11905548
rdf:type
n4:Context
rdf:value
To study AD, a variety of transgenic mouse models has been generated through the overexpression of the APP and/or the presenilins harboring one or several mutations found in familial AD.34,>>40<<,45,49,53, Although none of the AD transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and
n4:mentions
n2:8810256
Subject Item
_:vb11905549
rdf:type
n4:Context
rdf:value
To study AD, a variety of transgenic mouse models has been generated through the overexpression of the APP and/or the presenilins harboring one or several mutations found in familial AD.34,40,>>45<<,49,53, Although none of the AD transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and opportunities
n4:mentions
n2:11279122
Subject Item
_:vb11905550
rdf:type
n4:Context
rdf:value
34,40,45,>>49<<,53, Although none of the AD transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and opportunities to
n4:mentions
n2:9371838
Subject Item
_:vb11905551
rdf:type
n4:Context
rdf:value
34,40,45,49,>>53<<, Although none of the AD transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and opportunities to test
n4:mentions
n2:14985348
Subject Item
_:vb11905552
rdf:type
n4:Context
rdf:value
transgenic mice models reproduces the human condition exactly, the ability to study similar pathological processes in living animals has provided valuable insights into disease mechanisms and opportunities to test therapeutic approaches.>>11<< The AD mouse models have been key to understanding the roles of soluble Aβ oligomers in disease pathogenesis, as well as of the relationship between Aβ and Tau pathologies.
n4:mentions
n2:20101721
Subject Item
_:vb11905553
rdf:type
n4:Context
rdf:value
as of the relationship between Aβ and Tau pathologies. Data obtained from the comparison of different AD mouse lines indicate that the onset and the severity of the Aβ deposits are directly linked to the level of soluble Aβ1-42 peptide.>>42<<,43,47,58,59,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
n4:mentions
n2:10195221
Subject Item
_:vb11905554
rdf:type
n4:Context
rdf:value
of the relationship between Aβ and Tau pathologies. Data obtained from the comparison of different AD mouse lines indicate that the onset and the severity of the Aβ deposits are directly linked to the level of soluble Aβ1-42 peptide.42,>>43<<,47,58,59,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
n4:mentions
n2:16549764
Subject Item
_:vb11905555
rdf:type
n4:Context
rdf:value
the relationship between Aβ and Tau pathologies. Data obtained from the comparison of different AD mouse lines indicate that the onset and the severity of the Aβ deposits are directly linked to the level of soluble Aβ1-42 peptide.42,43,>>47<<,58,59,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
n4:mentions
n2:9427614
Subject Item
_:vb11905556
rdf:type
n4:Context
rdf:value
42,43,47,>>58<<,59,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
n4:mentions
n2:16876915
Subject Item
_:vb11905557
rdf:type
n4:Context
rdf:value
42,43,47,58,>>59<<,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
n4:mentions
n2:19215301
Subject Item
_:vb11905558
rdf:type
n4:Context
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42,43,47,58,59,>>63<<,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
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42,43,47,58,59,63,>>64<<,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
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42,43,47,58,59,63,64,>>83<<,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
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42,43,47,58,59,63,64,83,>>84<< There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.
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42,43,47,58,59,63,64,83,84 There is accumulating evidence from AD transgenic mice that intraneuronal Aβ1-42 triggers early neuronal loss as well as synaptic deficits.>>63<<, Studies in a transgenic animal model of AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss,69 which is in accordance with the hypothesis that synaptic loss is one of
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63, Studies in a transgenic animal model of AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss,>>69<< which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis.
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AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss,69 which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis.>>37<<,101-104 Furthermore, evidence from AD transgenic mouse models supports the notion that Aβ may directly or indirectly interact with Tau to accelerate neurofibrillary tangle formation.
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that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss,69 which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis.37,>>101<<-104 Furthermore, evidence from AD transgenic mouse models supports the notion that Aβ may directly or indirectly interact with Tau to accelerate neurofibrillary tangle formation.
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is one of the earliest events in AD pathogenesis.37,101-104 Furthermore, evidence from AD transgenic mouse models supports the notion that Aβ may directly or indirectly interact with Tau to accelerate neurofibrillary tangle formation.>>62<<,105 Finally, the AD transgenic models may allow to define and evaluate potential drug targets and to develop therapeutic strategies that might interfere or delay the onset of AD.
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one of the earliest events in AD pathogenesis.37,101-104 Furthermore, evidence from AD transgenic mouse models supports the notion that Aβ may directly or indirectly interact with Tau to accelerate neurofibrillary tangle formation.62,>>105<< Finally, the AD transgenic models may allow to define and evaluate potential drug targets and to develop therapeutic strategies that might interfere or delay the onset of AD.
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62,105 Finally, the AD transgenic models may allow to define and evaluate potential drug targets and to develop therapeutic strategies that might interfere or delay the onset of AD.>>106<<
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