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

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 (A beta) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although A beta is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which A beta leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of A beta 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 A beta clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma A beta ELISAs are discussed, as are the more promising results of A beta imaging by positron emission tomography. Current knowledge of A beta-binding proteins and A beta-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 A beta remains an attractive therapeutic strategy, and improved understanding of A beta clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.