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

K.A. Bates, Giuseppe Verdile, Q-X. Li, D. Ames, P. Hudson, C.L. Masters, Ralph Martins

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    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-β (Aβ) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Aβ is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Aβ leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Aβ 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 Aβ clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Aβ ELISAs are discussed, as are the more promising results of Aβ imaging by positron emission tomography. Current knowledge of Aβ-binding proteins and Aβ-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 Aβ remains an attractive therapeutic strategy, and improved understanding of Aβ clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.Molecular Psychiatry (2009) 14, 469–486; doi:10.1038/mp.2008.96; published online 16 September 2008
    Original languageEnglish
    Pages (from-to)469-486
    JournalMolecular Psychiatry
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - 2009

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