Cholesterol in Alzheimers Disease: Unresolved Questions

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 beta- and gamma-secretase cleavage of APP with altered Abeta 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, Ca(2+) 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 Abeta-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Abeta generation and cell resistance against Abeta 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.

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

“…Importantly, patients with AD have elevated circulating cholesterol [4,98], and ACAT1 is elevated in the blood [99] and in fibroblasts [100] from AD patients, but the reason for these observations is currently unclear. We suggest that altered communication between the MAM and mitochondria in AD results in increased ACAT1 activity, thereby affecting circulating cholesterol levels and Aβ production.…”

“…While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-ties are routinely detected in patients, including elevated cholesterol [4], altered fatty acid [5,6], glucose [7,8], and phospholipid [9] metabolism, aberrant calcium homeostasis [10], and mitochondrial dysfunction [11]. These features of AD have received far less attention because of the lack of direct links to the amyloid cascade, and have engendered numerous competing hypotheses to explain the pathogenesis of AD.…”

A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75NTR

“…137 Membrane biosynthesis could be compromised by specific allelic forms of ApoE, the main cholesterol carrier in the brain. 138 ApoE has been proposed to deliver lipids to neurites and growth cones for membrane biosynthesis in regenerating peripheral nerve, 139 and a virtual absence of NGF-dependent nerve sprouting has been observed in ApoE knock-out mice. 140 Accordingly, the presence of the AD risk allele ApoE4 results in a decrease of spine density and length and dendritic complexity in cortical neurons in vivo.…”

Manipulation of Lipid Rafts in Neuronal Cells~!2009-09-18~!2009-12-16~!2010-03-19~!

“…Lipid rafts have been attracted attention in neurodegeneration, such as Prion diseases, Parkinson`s disease and especially in AD [46][47][48]. Recently, alterations in lipid rafts isolated from AD brain were reported [49], including the localization of active -secretase in lipid rafts in human brain [50].…”