Regulation of cerebral cholesterol metabolism in Alzheimer disease

Abstract

Alzheimer disease (AD) is an age-related neurodegenerative disorder that manifests as a progressive loss of memory and deterioration of higher cognitive functions. Alzheimer disease is characterized by accumulation in the brain of the β-amyloid peptide generated by β- and γ-secretase processing of amyloid precursor protein. Epidemiological studies have linked elevated plasma cholesterol and lipoprotein levels in midlife with AD development. Cholesterol-fed animal models exhibit neuropathologic features of AD including accumulation of β-amyloid peptide. Specific isoforms of the cholesterol transporter apolipoprotein E are associated with susceptibility to AD. Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown. This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo.

FIGURE 1. Aβ formation in the brain

Aβ is formed by the sequential cleavage of its parent protein, APP, by two enzymes, BACE-1 and γ-secretase in the membrane. β-cleavage of APP occurs at the N-terminus of Aβ. This cleavage releases a membrane-associated fragment of 99 amino acids which is then further processed at a second site within its transmembrane domain by γ-secretase to release the Aβ peptide which can be 38–42 amino acids in length. Newly generated molecules of Aβ then aggregate into plaques.

FIGURE 2. The role of cholesterol metabolism in AD pathogenesis

The cholesterol pool in the brain contains cholesterol synthesized de novo and small amounts delivered from the periphery by HDLs that cross the BBB. Cholesterol binds to both APP and Aβ, and elevated levels of cholesterol increase amyloid plaque formation. HMG-CoA reductase regulates de novo cholesterol biosynthesis, while CYP46A1 and CYP27A1 mediate formation of 24S- and 27-hydroxycholesterol, respectively. Accumulation of these oxysterols inhibits aggregation of Aβ and activates LXRs. Aβ aggregation has an inhibitory effect on the expression of ABCA1, while LXR ligation upregulates ABCA1. ApoE-containing HDL-like particles inhibit the aggregation of Aβ, whereas free apoE has been shown to promote Aβ aggregation.