Cholinergic forebrain degeneration in the APPswe/PS1ΔE9 transgenic mouse

Perez, Sylvia E.; Dar, Saleem; Ikonomović, Miloš D.; DeKosky, Steven T.; Mufson, Elliott J.

doi:10.1016/j.nbd.2007.06.015

Cited by 88 publications

(101 citation statements)

References 98 publications

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“…However, even in the Tg lines with less aggressive A␤ pathology, aberrant expression of cell-cycle-related proteins occur in the 5-HT and NA neurons but not in the cholinergic neurons , suggesting that MAergic neurons are particularly vulnerable to increased levels of A␤. Consistent with this view, a recent report shows that despite axonal abnormalities, Ach neurons do not show degenerative changes in the aged APPswe/PS1⌬E9 mouse model (Perez et al, 2007). Although a complete analysis of the Ach system is in progress, our initial analyses of Ach afferents also indicate that Ach fibers are more preserved than the MAergic afferents and (supplemental Fig.…”

Section: Discussionsupporting

confidence: 85%

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Liu¹,

Yoo²,

Savonenko³

et al. 2008

J. Neurosci.

181

169

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␤-Amyloid (A␤) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A␤ pathology, including A␤ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A␤ neurotoxicity indicated by in vitro studies, mouse models with significant A␤ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A␤ pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1⌬E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A␤ deposition in the APPswe/ PS1⌬E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (ϳ50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A␤ or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of A␤ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

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Section: Discussionsupporting

confidence: 85%

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Liu¹,

Yoo²,

Savonenko³

et al. 2008

J. Neurosci.

181

169

View full text Add to dashboard Cite

show abstract

“…1, lanes 1 and 3), and as expected, KO mice did not express this enzyme (lanes 2 and 4). Previous examination of neuropathology in this mouse model of AD has revealed limited neuritic dystrophy without widespread loss of neurons (16), which may explain the normal levels of 24-hydroxylase in WT/AD animals. Blotting with an antiserum that recognized the humanized APP revealed expression in AD mice only and showed that the level of this protein was not altered by the presence or absence of 24-hydroxylase (see lanes 3 and 4).…”

Section: Analysis Of Proteins Related To Cholesterol Metabolism and Admentioning

confidence: 81%

Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan

Halford

Russell

2009

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in cellular cholesterol synthesis or content in cultured neurons affect the cleavage of amyloid precursor protein to amyloidogenic A␤ 40 and A␤42 peptides characteristic of Alzheimer's disease. To determine whether a decrease in cholesterol synthesis affects amyloid precursor protein processing in vivo, we crossed cholesterol 24-hydroxylase knockout mice, which exhibit a 50% reduction in brain sterol synthesis, with transgenic mice [B6.CgTg(APPswe, PSEN1E9)85Dbo/J] that develop Alzheimer's diseaselike pathology. Amyloid precursor protein expression and amyloid plaque deposition in the cortex and hippocampus of male and female Alzheimer's disease mice between the ages of 3 to 15 months were similar in the presence and absence of cholesterol 24-hydroxylase. A modest but statistically significant decline in insoluble A␤ 42 peptide levels was detected in the hippocampus of 12-month-old knockout/Alzheimer's disease males. The levels of insoluble A␤ 40 and A␤42 peptides in 15-month-old knockout/ Alzheimer's disease females were also reduced slightly. Although amyloid plaque accumulation did not affect brain sterol or fatty acid synthesis rates in 24-hydroxylase WT or knockout mice, loss of one or both cholesterol 24-hydroxylase alleles increased longevity in Alzheimer's disease mice. These studies suggest that reducing de novo cholesterol synthesis in the brain will not substantially alter the course of Alzheimer's disease, but may confer a survival advantage.amyloid plaque ͉ cholesterol 24-hydroxylase ͉ P450 ͉ statin A lzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system that affects a growing percentage of the elderly population. AD is characterized by gradual loss of cognitive function leading to death, and at the biochemical level, by the deposition of aberrantly folded proteins in the cortex and hippocampus of the brain (1). These protein deposits, termed amyloid plaques and neurofibrillary tangles, contain proteolytic fragments of the amyloid precursor protein (APP) and hyperphosphorylated forms of the tau microfilament protein, respectively (2, 3).Mutations in genes encoding proteins that produce amyloid plaques such as APP, presenilin 1, and presenilin 2 cause early onset forms of AD (1), as do altered versions of several proteins with less well-defined roles in the pathogenesis of the disorder, such as apolipoprotein E (ApoE). There are 3 major isoforms of ApoE, referred to as ApoE2, E3, and E4, and individuals who inherit one of more copies of the gene specifying ApoE4 are predisposed to earlier ages of AD onset (4). ApoE plays an important role in cholesterol metabolism in peripheral tissues (5), and this function has led to the notion that alterations in brain cholesterol metabolism may affect the inception or progression of AD. In support of this hypothesis, some but not all epidemiological studies show that subjects who take statins, a class of drugs that reduce plasma cholesterol levels by inhibiting de novo cholesterol synthesis, have altered sus...

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“…26,57 Selective loss of monoaminergic neurons is evident in aged animals, starting at age 18 months. 26 In striking contrast, the cholinergic neuron number remains unchanged, 57 Thus, the APPswe/ PS1ΔE9 transgenic mouse model failed to show significant cholinergic/monoaminergic degeneration or learning and memory deficits during our study. Given this inherent weak ness in the APPswe/PS1ΔE9 Alzheimer disease model, the ef fect of ASS234 was related only to amyloid plaque load.…”

Section: Limitationsmentioning

confidence: 99%

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

Serrano

Herrero-Labrador

Futch

et al. 2017

JPN

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Cholinergic forebrain degeneration in the APPswe/PS1ΔE9 transgenic mouse

Cited by 88 publications

References 98 publications

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

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