Role of apolipoprotein E in neurodegenerative diseases

Abstract

Apolipoprotein E (APOE) is a lipid-transport protein abundantly expressed in most neurons in the central nervous system. APOE-dependent alterations of the endocytic pathway can affect different functions. APOE binds to cell-surface receptors to deliver lipids and to the hydrophobic amyloid-β peptide, regulating amyloid-β aggregations and clearances in the brain. Several APOE isoforms with major structural differences were discovered and shown to influence the brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review will summarize the updated research progress on APOE functions and its role in Alzheimer's disease, Parkinson's disease, cardiovascular diseases, multiple sclerosis, type 2 diabetes mellitus, Type III hyperlipoproteinemia, vascular dementia, and ischemic stroke. Understanding the mutations in APOE, their structural properties, and their isoforms is important to determine its role in various diseases and to advance the development of therapeutic strategies. Targeting APOE may be a potential approach for diagnosis, risk assessment, prevention, and treatment of various neurodegenerative and cardiovascular diseases in humans.

Keywords: apolipoprotein E; diseases; pathogenesis.

Figure 1

APOE formation and its role in redistribution of lipids to the cells of CNS: the neuropathological effects of the neurotoxic APOE fragments. Notes: ① APOE mainly produced by astrocytes, either pericytes, microglia, or under certain pathological conditions (stressors, injurious agents, etc). ② The role of APOE in the production of Aβ in association with APP. ③ The result of APOE fragmentation is associated with cytoskeletal disruption and mitochondrial dysfunction. ④ APOE isoform-specifically and Aβ-induced lysosomal leakage and apoptosis. Abbreviations: Aβ, amyloid-β; APOE, apolipoprotein E; APP, amyloid precursor protein; LRP, lipoprotein receptor-related protein 1; CNS, central nervous system.

Figure 2

Schematic Illustration of structural and functional regions of APOE. Notes: (A) Location and structure of the APOE gene on chromosome 19. (B) APOE protein is a polypeptide chain with 299 amino acids consisting of a receptor-binding region (residues 136–150) in the N-terminal domain (residues 1–167) and a lipid-binding region (residues 244–272) in the C-terminal domain (residues 206–299). (C) Three major APOE isoforms are located at residues 112 and 158 (red circles), where APOE2 has Cys residues at both positions, APOE3 has a Cys residue at 112 and an Arg residue at 158, and APOE4 has Arg residues at both positions. Abbreviation: APOE, apolipoprotein E.

Figure 3

APOE is associated with disease progression in various conditions. Abbreviation: APOE, apolipoprotein E.