Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Abstract

Purpose of reviewAPOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease.Recent findingsApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis.SummaryEmerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

“…LXRs and the genes regulated by LXRs such as ABCA1, ABCG1 and APOE, modulate intracellular cholesterol content and cholesterol efflux and have been associated with AD pathogenesis 42 . Our analysis also identified PPARA as putative regulator of ABCA1 and recent studies have demonstrated that PPAR pathway activation increased ABCA1 levels, that in turn lead to APOE lipidation and amyloid ß clearance 43 . We also identified transport of taurine as an important factor from the metabolic analysis.…”

A human single-cell atlas of the Substantia nigra reveals novel cell-specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders

“…We identified a unique cell type-specific signal between microglia and genetic variants associated with High-density lipoprotein (HDL) cholesterol level (q MAGMA = 0.046) (Figure 2a). Given the role of lipids in AD 15,16 , we asked whether the HDL cholesterol association was related to the association between AD risk and microglia gene expression (Figure 2a). However, conditional analysis suggests distinct genetics underlie the associations of AD and HDL cholesterol levels with microglia ( Supplementary Figure 8).…”

Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?

“…Moreover, the single amino acid difference coded by APOE ε2, ε3 and ε4 alleles affects the structures of apoE isoforms and influence their ability to bind lipids, receptors, and Aβ [37]. Aβ accumulation in human brain follows the pattern of APOE ε4 > APOE ε3 > APOE ε2 [41] and Aβ clearance is promoted by lipidation of apoE [38]. In addition to preventing Aβ oligomer formation and inducing Aβ degradation, lipidated apoE promotes Aβ efflux via blood‐brain barrier and might enhance peripheral clearance through apoE‐containing HDL particles [38].…”

“…APOE ε3 . APOE ε2 [41] and Ab clearance is promoted by lipidation of apoE [38]. In addition to preventing Ab oligomer formation and inducing Ab degradation, lipidated apoE promotes Ab efflux via bloodbrain barrier and might enhance peripheral clearance through apoE-containing HDL particles [38].…”