Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease

Figure 2

Cholesterol transport in the CNS. APOE is synthesized by astrocytes and assembles free cholesterol (FC) and phospholipids (PLs) to form HDL-like particles. (1) Lipidation of these lipoparticles is facilitated via the mobilization and distribution of lipids to the cell surface by ABCA1/G1. Once secreted in the extracellular space, these HDL-like particles are directed either toward the circulation through the BBB and/or to neurons requiring lipids. (2) These APOE-HDL-like particles are recognized and endocytosed by members of the cell surface LDLR family (LDLR, LRP, APOER2, VLDLR), and (3) the FC is released within neurons and can be used for neurite elongation and/or synaptogenesis (4). As a result of lipid internalization, the endogenous synthesis of cholesterol within neurons (via the HMGCR pathway) is repressed (5). Excess cholesterol will be removed from neurons through its conversion into 24S-hydroxycholesterol (24S-OH) which is mediated by cholesterol 24S-hydroxylase (CYP46) (6). This sterol can now freely cross lipophilic membranes of the BBB and exit the brain for elimination (7). APOE or E: apolipoprotein E; BBB: blood-brain barrier; RER: rough endoplasmic reticulum; HMGCR: 3-hydroxy-3-methylglutaryl coenzyme A reductase; HDL: high-density lipoprotein; LDLR: low-density lipoprotein receptor.