Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Abstract

Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-beta (Abeta) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Abeta is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Abeta leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Abeta are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Abeta clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Abeta ELISAs are discussed, as are the more promising results of Abeta imaging by positron emission tomography. Current knowledge of Abeta-binding proteins and Abeta-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Abeta remains an attractive therapeutic strategy, and improved understanding of Abeta clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.