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

Molecular Psychiatry volume 14, pages 469–486 (2009)Cite this article

A Corrigendum to this article was published on 18 November 2009

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.

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Acknowledgements

This work was supported through research grant funding from the National Health and Medical Research Council of Australia, the Dementia Collaborative Research Centre, the Australian Biomarkers, Imaging and Lifestyle Flagship study of Ageing and the National Institutes of Health (project ID 52070400). KAB, GV and RNM acknowledge the Centre of Excellence for Alzheimer's Disease Research and Care and The McCusker Foundation for Alzheimer's disease Research for additional support. We also acknowledge editorial assistance from Miss Tamar Berger.

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Authors and Affiliations

  1. School of Exercise, Biomedical and Health Science, Edith Cowan University, Joondalup, WA, Australia

    K A Bates, G Verdile & R N Martins

  2. Sir James McCusker Alzheimer's disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia

    K A Bates, G Verdile & R N Martins

  3. School of Psychiatry and Clinical Neuroscience, University of Western Australia, Nedlands, WA, Australia

    K A Bates, G Verdile & R N Martins

  4. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

    Q-X Li & C L Masters

  5. The Mental Health Research Institute of Victoria, Parkville, VIC, Australia

    Q-X Li & C L Masters

  6. Centre for Neuroscience, The University of Melbourne, Parkville, VIC, Australia

    Q-X Li

  7. National Ageing Research Institute, Royal Melbourne Hospital, Parkville, VIC, Australia

    D Ames

  8. AIBL Commercialisation National Neuroscience Facility, South Melbourne, VIC, Australia

    P Hudson

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  1. K A Bates
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Correspondence to R N Martins.

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Bates, K., Verdile, G., Li, QX. et al. Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry 14, 469–486 (2009). https://doi.org/10.1038/mp.2008.96

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  • DOI: https://doi.org/10.1038/mp.2008.96

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