Dyslipidemia and the Risk of Alzheimer's Disease.
ABSTRACT Whether cholesterol is implicated in the pathogenesis of Alzheimer's disease (AD) is still controversial. Several studies that explored the association between lipids and/or lipid-lowering treatment and AD indicate a harmful effect of dyslipidemia on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E (APOE), apolipoprotein J (APOJ, CLU), ATP-binding cassette subfamily A member 7(ABCA7), and sortilin-related receptor (SORL1). Functional cell biology studies further support a critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase resulting in altered Aβ production. However, conflicting evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, randomized clinical trials observing no beneficial effect of statin therapy, and cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol level is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits colocalization of β-secretase 1 and Aβ precursor protein in nonraft membrane domains, thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this article is to provide a comprehensive review of the findings of epidemiological, genetic, and cell biology studies aiming to elucidate the role of cholesterol in the pathogenesis of AD.
SourceAvailable from: Cristina Legido-Quigley[Show abstract] [Hide abstract]
ABSTRACT: There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.Translational Psychiatry 10/2014; DOI:10.1038/tp.2014.127 · 4.36 Impact Factor
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ABSTRACT: Most neurodegenerative diseases are characterized by the presence of protein aggregates. Alzheimer's disease (AD) is the most common cause of dementia in people over age 60. One of the histopathological hallmarks of AD is the presence of tau protein aggregates. Historically it has been thought that paired helical filaments (PHFs) were the toxic form of tau that assembled to form neurofibrillar tangles (NFTs), but recently there has been evidence that tau oligomers, which form before PHFs and NFTs, could be the structures mediating the neurodegeneration even before the fibrillary tau is deposited. Here we discuss the recent advances in tau oligomers research and its implications on AD and other tauopathies and the mechanisms of tau turnover by the principal protein clearance systems: Proteasome and autophagy, as well as the potential use of tau oligomers as drug targets for the development of new therapeutic approaches.ACS Chemical Neuroscience 09/2014; DOI:10.1021/cn500148z · 4.21 Impact Factor
Article: Lipid Membrane Domains In The Brain.[Show abstract] [Hide abstract]
ABSTRACT: The brain is characterized by the presence of cell types with very different functional specialization, but with the common trait of a very high complexity of structures originated by their plasma membranes. Brain cells bear evident membrane polarization with the creation of different morphological and functional subcompartments, whose formation, stabilization and function require a very high level of lateral order within the membrane. In other words, the membrane specialization of brain cells implies the presence of distinct membrane domains. The brain is the organ with the highest enrichment in lipids like cholesterol, glycosphingolipids, and the most recently discovered brain membrane lipid, phosphatidylglucoside, whose collective behavior strongly favors segregation within the membrane leading to the formation of lipid-driven membrane domains. Lipid-driven membrane domains function as dynamic platforms for signal transduction, protein processing, and membrane turnover. Essential events involved in the development and in the maintenance of the functional integrity of the brain depend on the organization of lipid-driven membrane domains, and alterations in lipid homeostasis, leading to deranged lipid-driven membrane organization, are common in several major brain diseases. In this review, we summarize the forces behind the formation of lipid membrane domains and their biological roles in different brain cells. This article is part of a Special Issue entitled Brain Lipids. Copyright © 2015. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 02/2015; DOI:10.1016/j.bbalip.2015.02.001 · 4.50 Impact Factor