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In multiple pathways affecting neuropathology, including Alzheimer\u2019s disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid \u03b2 peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N- and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of \u201cstructure correctors\u201d to convert apoE4 to an \u201capoE3-like\u201d molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and \u201cmitochondrial protectors\u201d to prevent cellular energy disruption.<\/jats:p>","DOI":"10.1073\/pnas.0600549103","type":"journal-article","created":{"date-parts":[[2006,3,28]],"date-time":"2006-03-28T01:34:47Z","timestamp":1143509687000},"page":"5644-5651","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":714,"title":["Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"103","author":[{"given":"Robert W.","family":"Mahley","sequence":"first","affiliation":[{"name":"*Gladstone Institute of Neurological Disease and"},{"name":"Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158; 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