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.