title: Apolipoprotein e sets the stage: response to injury triggers neuropathology.
abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease and is associated with poor clinical outcome following traumatic brain injury and other neuropathological disorders. Protein instability and an isoform-specific apoE property called domain interaction are responsible for these neuropathological effects. ApoE4 is the most neurotoxic isoform and can induce neuropathology through various cellular pathways. Neuronal damage or stress induces apoE synthesis as part of the repair response; however, when apoE4 is expressed in neurons, its unique conformation makes it susceptible to proteolysis, resulting in the generation of neurotoxic fragments. These fragments cause pathological mitochondrial dysfunction and cytoskeletal alterations. Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. rmahley@gladstone.ucsf.edu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mahley
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001930:Brain Injuries / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009422:Nervous System Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport
chemical_list: D001057:Apolipoproteins E