Abstract
The role of cholesterol as a susceptibility factor or a protective agent in neurodegeneration and, more generally, in amyloid-induced cytotoxicity is still controversial. Epidemiological studies on the hypercholesterolemia-AD risk relation and some reports indicating a beneficial effect of statin therapy suggest cholesterol as a susceptibility factor in AD. The ApoE4 genotype as a prevalent genetic risk factor for AD and the function of ApoE as main cholesterol carrier in the brain also underlie a close cholesterol load-AD risk relation. Finally, cell biology evidences support a critical involvement of lipid raft cholesterol in the modulation of β- and γ-secretase cleavage of APP with altered Aβ production. However, little exchange does exist between circulating and brain cholesterol, the latter arising from endogenous synthesis. In addition, increasing evidence supports the idea that amyloid cytotoxicity in most cases is initiated by oligomer recruitment at the cell membrane with loss of membrane integrity, Ca2+ ingress into the cell, oxidative stress and apoptosis. In such a scenario, increased membrane cholesterol seems to be protective by disfavouring aggregate binding to the membrane. Recent findings also indicate that a reduction of cellular cholesterol favours co-localization of BACE1 and APP in non-raft membrane domains and hinders generation of plasmin, an Aβ-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Aβ generation and cell resistance against Aβ oligomer toxicity. These data confirm previous findings indicating a reduction of the cholesterol/ phospholipid ratio in aged and AD brains. The aim of this review is to critically discuss some of the main results reported in the recent years in this field supporting a role of cholesterol either as a susceptibility factor or as a protective agent in AD.
Keywords: Alzheimer's disease, cholesterol, Aβ peptides, APP, neurodegeneration, amyloid
Current Alzheimer Research
Title: Cholesterol in Alzheimers Disease: Unresolved Questions
Volume: 6 Issue: 1
Author(s): Massimo Stefani and Gianfranco Liguri
Affiliation:
Keywords: Alzheimer's disease, cholesterol, Aβ peptides, APP, neurodegeneration, amyloid
Abstract: The role of cholesterol as a susceptibility factor or a protective agent in neurodegeneration and, more generally, in amyloid-induced cytotoxicity is still controversial. Epidemiological studies on the hypercholesterolemia-AD risk relation and some reports indicating a beneficial effect of statin therapy suggest cholesterol as a susceptibility factor in AD. The ApoE4 genotype as a prevalent genetic risk factor for AD and the function of ApoE as main cholesterol carrier in the brain also underlie a close cholesterol load-AD risk relation. Finally, cell biology evidences support a critical involvement of lipid raft cholesterol in the modulation of β- and γ-secretase cleavage of APP with altered Aβ production. However, little exchange does exist between circulating and brain cholesterol, the latter arising from endogenous synthesis. In addition, increasing evidence supports the idea that amyloid cytotoxicity in most cases is initiated by oligomer recruitment at the cell membrane with loss of membrane integrity, Ca2+ ingress into the cell, oxidative stress and apoptosis. In such a scenario, increased membrane cholesterol seems to be protective by disfavouring aggregate binding to the membrane. Recent findings also indicate that a reduction of cellular cholesterol favours co-localization of BACE1 and APP in non-raft membrane domains and hinders generation of plasmin, an Aβ-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Aβ generation and cell resistance against Aβ oligomer toxicity. These data confirm previous findings indicating a reduction of the cholesterol/ phospholipid ratio in aged and AD brains. The aim of this review is to critically discuss some of the main results reported in the recent years in this field supporting a role of cholesterol either as a susceptibility factor or as a protective agent in AD.
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Cite this article as:
Stefani Massimo and Liguri Gianfranco, Cholesterol in Alzheimers Disease: Unresolved Questions, Current Alzheimer Research 2009; 6 (1) . https://dx.doi.org/10.2174/156720509787313899
DOI https://dx.doi.org/10.2174/156720509787313899 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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