Evidence for impaired amyloid β clearance in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of extracellular plaques and intracellular tangles. Recent studies support the hypothesis that the accumulation of amyloid beta (Aβ) peptide within the brain arises from an imbalance of the production and clearance of Aβ. In rare genetic forms of AD, this imbalance is often caused by increased production of Aβ. However, recent evidence indicates that, in the majority of cases of AD, Aβ clearance is impaired. Apolipoprotein E (ApoE), the dominant cholesterol and lipid carrier in the brain, is critical for Aβ catabolism. The isoform of ApoE and its degree of lipidation critically regulate the efficiency of Aβ clearance. Studies in preclinical models of AD have demonstrated that coordinately increasing levels of ApoE and its lipid transporter, ABCA1, increases the clearance of Aβ, suggesting that this pathway may be a potential therapeutic target for AD.

Figure 1

Mechanisms of amyloid beta (Aβ) clearance are mediated by apolipoprotein E (ApoE) and ATP-binding cassette A1 (ABCA1). Activation of nuclear hormone receptors - liver × receptor (LXR), peroxisome proliferator-activated receptor gamma (PPARγ), and retinoid × receptor (RXR) - induces the expression of ApoE and ABCA1. The lipidation of ApoE by ABCA1 stimulates the degradation of Aβ through multiple pathways: extracellular degradation by insulin-degrading enzyme (IDE) or uptake by microglial cells and subsequent lysosomal degradation. Aβ can also be cleared from the central nervous system by binding to ApoE receptors such as low-density lipoprotein receptor (LDLR) or LDLR-related protein 1 (LRP1) that mediate transport across the blood-brain barrier.