Apolipoprotein E in lipid metabolism and neurodegenerative disease

Abstract

Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.

Keywords: Alzheimer's disease; apolipoprotein E; lipid metabolism; neurodegenerative disease.

Figure 1.. Numerous nonsynonymous APOE mutations modify neurological disease risk.

The mature APOE protein consists of two primarily alpha-helical domains (light grey sections), connected by an intrinsically disordered hinge region (dark grey bar; residues 200-215). The N-terminal domain contains the low-density lipoprotein receptor binding site (diagonal stripes; residues 136-150) while the C-terminal domain contains sites for lipid binding (dark grey; residues 244-272). In relation to APOE3 (C112; R158), risk mutations are depicted in red, protective mutations in blue, and mutations of unknown neurological effect are in grey. Dashed lines indicate predicted or mild directional effects. Diamond-headed pins reflect variants on an APOE4 (C112R) background. This diagram was adapted from data in the Alzforum APOE mutations database. Abbreviations: fs represents a frameshift mutation, ChC stands for Christchurch, delins is a deletion-insertion mutation.

Figure 2.. APOE isoforms impact communication between glia and neurons.

(A) Astrocytes provide metabolic support to neurons by supplying neurons with lipids such as cholesterol and metabolizing lipid species secreted by neurons. These activities are impaired by APOE4. (B) APOE4, but not APOE3, impairs calcium signaling in both microglia and neurons. APOE4 microglia also accumulate triglycerides, exhibit decreased purinergic signaling, and secrete proinflammatory cytokines. (C) Oligodendrocytes myelinate neurons. APOE4 oligodendrocytes display lower viability and intracellular cholesterol accumulation which leads to decreased myelination capacity. This figure was created using Biorender.com.