Cholesterol in Alzheimer’s Disease: Unresolved Questions
Pp. 58-99 (42)
Massimo Stefani and Gianfranco Liguri
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-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 oligomer nucleation, 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 point at a key role performed by lipid rafts and their proteins and 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.
Alzheimer’s disease, Aβ peptides, APP, neurodegeneration, amyloid,
Department of Biochemical sciences, University of Florence, Viale Morgagni m50, 50134 Florence, Italy.