Astrocyte lipoproteins, effects of apoE on neuronal function, and role of apoE in amyloid-beta deposition in vivo.
The genetic association between the E4 isoform of apolipoprotein E (apoE) and increased risk for Alzheimer's disease (AD) has prompted interest in the neurobiology of apoE and the possible relationship between lipoprotein metabolism in the brain and neurodegenerative disease. ApoE, a product of astrocytes, is abundant in brain and in cerebrospinal fluid (CSF) where it is found in lipoproteins the size of large plasma high-density lipoproteins (HDL). Cultured astrocytes also secrete apoE/HDL, although the lipid and apoprotein composition of these nascent particles differs from that found in CSF, suggesting possible functional differences. In vitro studies have demonstrated isoform-specific effects of apoE on neurite outgrowth, neuronal plasticity, neurotoxicity, lipid peroxidation, oxidative injury, binding to cytoskeletal proteins, and interactions with amyloid-beta (Abeta), a primary component of senile plaques in AD. A number of these proposed functions have also been assessed in apoE -/- mice and transgenic mice expressing human apoE3 or apoE4. Importantly, analysis of transgenic mice overexpressing a mutant form of the human amyloid precursor protein (APP(V717F)) in the presence of mouse apoE, no apoE, or human apoE3 or E4 has demonstrated a critical and isoform-specific role for apoE in neuritic plaque formation, a pathologic hallmark of AD. Together, these data have provided important clues as to possible mechanism(s) by which apoE genotype modifies AD risk.
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA. fagana@neuro.wustl.edu
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Fagan
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Holtzman
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D020033:Protein Isoforms; D016875:tau Proteins