ABCA1, apoE and apoA-I as potential therapeutic targets for treating Alzheimer’s disease

Abstract

SUMMARY The association between apoE genotype and risk and age of onset for Alzheimer’s disease (AD) was first discovered in 1993. Innumerable studies since then have defined Aβ-dependent and Aβ-independent roles for apoE in AD pathogenesis. Although therapeutic approaches that specifically target apoE are not yet developed for AD, apoE may have a more fundamental role in brain physiology than previously appreciated. ApoE is the major apolipoprotein in the CNS, coordinating the uptake and delivery of lipids among various cell types in the brain. ApoE receives lipids from the membrane-bound cholesterol and phospholipid transporter ATP-binding cassette transporter A1 (ABCA1). Genetic and pharmacological methods to enhance ABCA1 activity generate lipid-rich apoE particles and provide cognitive and neuropathological benefits in animal models of AD. Recent studies on apoA-I, which is the major lipid acceptor for ABCA1 in peripheral tissues and is also present in the CNS, suggest that increasing apoA-I function may also have neuroprotective effects. In this article, we will discuss the potential of ABCA1, apoE and apoA-I as therapeutic targets for the treatment of AD.