Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.
Martins
Ian J
IJ
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Australia. r.martins@ecu.edu.au
Berger
Tamar
T
Sharman
Matthew J
MJ
Verdile
Giuseppe
G
Fuller
Stephanie J
SJ
Martins
Ralph N
RN
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D011973:Receptors, LDL / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001053:Apolipoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D002784:Cholesterol