Brain Cholesterol, Statins and Alzheimer’s Disease

Growing evidence suggests that cellular cholesterol homeostasis is causally involved in different steps leading to pathological events in the brain of Alzheimer’s Disease (AD) patients. It was previously demonstrated that the processing of the amyloid beta-peptide precursor protein (APP) is modulated by pronounced alterations in cellular cholesterol levels using statins or cholesterol extracting agents. However, a cholesterol-rich diet was found to enhance amyloid beta-peptide (Aβ) burden in the brain of transgenic mice without clearly affecting total brain cholesterol levels. Recent retrospective epidemiological studies have reported that the use of statins potentially suppresses the development of AD. Although some HMG-CoA reductase inhibitors seem to influence the central cholesterol pool in vivo, the above epidemiological findings are probably not linked to statin-induced changes in brain membrane cholesterol levels per se since not all statins active in preventing AD enter the central nervous system (CNS). Recently, we reported that different statins, regardless of their brain availability, induce alterations in cellular cholesterol distribution in the brain. Such pleiotropic, cholesterol-synthesis independent statin effects might be indirect and are possibly mediated at the blood-brain barrier (BBB) via nitric oxide (NO) or apolipoprotein E (ApoE).

Abbreviations

Aβ:amyloid beta-peptide

AD:Alzheimer’s disease

ApoE:apolipoprotein E

APP₃:amyloid beta-peptide precursor protein

BBB:blood-brain barrier

CHD:coronary heart disease

CHOD-PAP-cholesteroloxidase-peroxidase-aminophenazon-method:phenol-method

CNS:central nervous system

CSF:cerebrospinal fluid

DHE:dehydroergosterol

ER :endoplasmatic reticulum

HMG-CoA:hydroxymethylglutaryl-coenzyme A

MβCD:methyl-beta-cyclodextrin

NO:nitric oxide

NOs:nitric oxide synthase

PUFA:polyunsaturated fatty acid

SMC:smooth muscle cell

SPM:synaptosomal plasma membrane

SUV:small unilammelar vesicle

TNBS:trinitrobenzensulfonic acid

Key words

Cholesterol - Statins - Brain - Membrane - Alzheimer's Disease

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