Cholesterol and Alzheimer’s Disease

Abstract

The relationship between the abundance of cholesterol in the brain and Alzheimer’s disease (AD) progression is a controversial one, although cholesterol is necessary for neuronal function. Because the ε4 allele of the gene encoding apolipoprotein E (apoE), a lipoprotein that transports cholesterol, is a genetic risk factor for late-onset AD, Liu et al . investigated a link between amyloid precursor protein (APP), apoE, and cholesterol metabolism. Sequential cleavage of APP, a transmembrane protein, by β-secretase and γ-secretase releases amyloid β-peptide (Aβ) and the APP intracellular domain (AICD) into the extracellular space, where the former forms plaques. The authors found that the abundance of apoE (as measured by enzyme-linked immunosorbent assay) was lower in the brains of APP -deficient mice (APP-KO) and mice deficient in both APP and the related APLP2 (DKO) than in wild-type mice. Real-time polymerase chain reaction and Western blotting analyses showed that the abundance of the apoE receptor LRP1 was higher in APP-KO and DKO mice than in wild-type controls. Brain-specific deletion of LRP1 resulted in the higher abundance of apoE in the brains of these mice than in the brains of wild-type mice. Deletion of the gene encoding β-secretase, which is required for Aβ production, had no effect on LRP1 abundance or function. However, deletion of both presenilin 1 ( PS1 ) and PS2 (PS DKO), which encode proteins critical to the function of γ-secretase, resulted in the higher abundance of LRP1 in PS DKO mice compared with that of wild-type mice. Further analysis showed that the AICD, released through γ-secretase activity, combined with the adaptor protein Fe65 and bound to the LRP1 promoter, inhibiting its expression. Thus, APP processing by γ-secretase results in the decreased abundance of LRP1, which results in the reduced uptake of apoE-complexed cholesterol. Together, these data suggest a role for APP in regulating apoE and cholesterol metabolism, through the lipoprotein receptor LRP1, which provides new therapeutic targets for treating AD. Q. Liu, C. V. Zerbinatti, J. Zhang, H.-S. Hoe, B. Wang, S. L. Cole, J. Herz, L. Muglia, G. Bu, Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56 , 66-78 (2007). [PubMed]