title: [Cholesterol and Alzheimer's disease].
abstract: Epidemiological, biochemical and pharmacological investigations provide increasing number of evidences that altered cholesterol metabolism contributes to the development of Alzheimer's disease. The objective of the present paper is to review existing information about the links of cholesterol and amyloid metabolism from the clinical and proposed etiological viewpoints of the most frequent dementing disorder in Hungary. Beta-amyloid peptide, the major component of the senile plaques in the Alzheimer's disease brains is the end product of the abnormal post-translational processing of its precursor, called amyloid precursor protein. The compartmentation of the amyloid precursor protein molecule within the cell membrane is regulated by the cholesterol content of the bilayers. The amyloid precursor protein molecule could be present either in-, or outside of the membrane rafts. Any kind of process, which alters the compartmentation preference of the amyloid precursor protein molecule, by transferring it to the membrane rafts, favours beta- and gamma-secretase cleavage, and should be recognised as an amyloidogenic process. If the blood-brain barrier is intact, the brain is not able to take up the lipoprotein particles responsible for the transport of cholesterol. Instead of the active uptake, neurons and glial cells synthetize cholesterol de novo, in a process, where the rate limiting enzyme is 3-hydroxy-3-methylglutaryl coenzyme A. On the other hand, the brain specific CYP46A1 enzyme is responsible for the degradation of cholesterol into a water soluble metabolite, called 24S-OH cholesterol. The decreased CYP46A1 activity in the brain of Alzheimer's disease patients raises membrane cholesterol levels, and as a consequence the amyloid precursor protein is shifted and deposited in the cholesterol rich lipid rafts leading to beta-amyloid peptide specific metabolism. Among the polymorphic variants of the apolipoprotein E gene, the E4 allele is considered as a major risk factor for Alzheimer's disease. The E4 allele carrier Alzheimer's disease probands have increased amyloid burden, decreased beta-amyloid peptide degradation, and less effective neuronal repair mechanisms. Even as early as age 30, patients with Niemann-Pick Type C disease show clinical and neuropathological signs of Alzheimer's disease. The point mutation of the protein responsible for the endosomal transport of cholesterol is considered as a major cause of the beta-amyloid peptide deposition in the brain of Niemann-Pick Type C patients. One of the most exciting recent discovery, that Niemann-Pick Type C disease could be recognised as a disease model for Alzheimer's disease. New, promising cholesterol metabolism related therapeutic approaches are discussed, but it is emphasized that the clinical evidences regarding their efficacy in Alzheimer's disease are still missing.
authors.affiliation: Szegedi Tudományegyetem, Pszichiátriai Klinika,Alzheimer-kór Kutatócsoport, Szeged. kalmanj@nepsy.szote.u-szeged.hu
authors.forename: János
authors.initials: J
authors.lastname: Kálmán
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Janka
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008074:Lipoproteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009542:Niemann-Pick Diseases / Q000378:metabolism; D017354:Point Mutation; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; C030104:lipoprotein cholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase