Astrocyte lipoproteins, effects of apoE on neuronal function, and role of apoE in amyloid-β deposition in vivo

✍ Scribed by Anne M. Fagan; David M. Holtzman

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 86 KB
• Volume: 50
• Category: Article
• ISSN: 1059-910X
• DOI: 10.1002/1097-0029(20000815)50:4<297::aid-jemt9>3.0.co;2-c

✦ Synopsis

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-␤ (A␤), a primary component of senile plaques in AD. A number of these proposed functions have also been assessed in apoE Ϫ/Ϫ 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.