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) a nd increased risk for Alzheimer's disease (AD) has prompted interest in the neurobiology of apoE and the possible relationship between lipoprotein met abolism in the brain and neurodegenerative disease. ApoE, a product of astr ocytes, is abundant in brain and in cerebrospinal fluid (CSF) where it is f ound in lipoproteins the size of large plasma high-density lipoproteins (HD L). Cultured astrocytes also secrete apoE/HDL, although the lipid and apopr otein composition of these nascent particles differs from that found in CSF , suggesting possible functional differences. In vitro studies have demonst rated isoform-specific effects of apoE on neurite outgrowth, neuronal plast icity, neurotoxicity, lipid peroxidation, oxidative injury, binding to cyto skeletal proteins, and interactions with amyloid-P (AP), a primary componen t of senile plaques in AD. A number of these proposed functions have also b een assessed in apoE -/- mice and transgenic mice expressing human apoE3 or apoE4. Importantly, analysis of transgenic mice overexpressing a mutant fo rm of the human amyloid precursor protein (App(V717F)) in the presence of m ouse apoE, no apoE, or human apoE3 or E4 has demonstrated a critical and is oform-specific role for apoE in neuritic plaque formation, a pathologic hal lmark of AD. Together, these data have provided important clues as to possi ble mechanism(s) by which apoE genotype modifies AD risk. (C) 2000 Wiley-Li ss, Inc.