title: Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease.
abstract: APOE4 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.
  
  
  
  ApoE 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.
  
  
  
  Emerging 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.
authors.affiliation: aDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri bNeurobiology of Disease Graduate Program, Mayo Graduate School cDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D009473:Neuronal Plasticity; D014158:Transcription, Genetic
chemical_list: D001057:Apolipoproteins E