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Physiological Roles of Amyloid-β and Implications for its Removal in Alzheimer’s Disease

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Abstract

The underlying pathological cause of Alzheimer’s disease has been postulated to be an excess of amyloid-β (Aβ) which aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function and eventually leading to neuronal degeneration and dementia. As a result, therapeutic strategies have been developed that are designed to remove Aβ from the brain. Caution needs to be exercised concerning such strategies because, in addition to its presence in neuritic plaques, Aβ has a widespread distribution through the brain and body, even in cognitively normal individuals. Evidence indicates that instead of being a toxic peptide, soluble Aβ serves a variety of physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens. These physiological functions must be taken into account when strategies are developed to reduce Aβ load in Alzheimer’s disease. Ideally, such strategies should target forms of Aβ that are not bioavailable, such as fibrillar Aβ, or forms that are regarded to be overexpressed in Alzheimer’s disease (such as oligomers) while leaving normal soluble Aβ1–40 and β1–42 intact. At present none of the available therapeutic strategies appears to have such selectivity. Until these technical limitations and the uncertainties regarding the effect of depletion of Aβ from the brain are resolved, it would not be prudent to begin further clinical trials.

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Acknowledgements

We wish to thank the Department of Psychology, Monash University, Australia, for providing resources that assisted in the preparation of this review.

The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. School of Psychology, Psychiatry and Psychological Medicine, Monash University, Wellington Road, Clayton, Victoria, 3800, Australia

    Glenda M. Bishop &  Stephen R. Robinson

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Bishop, G.M., Robinson, S.R. Physiological Roles of Amyloid-β and Implications for its Removal in Alzheimer’s Disease. Drugs Aging 21, 621–630 (2004). https://doi.org/10.2165/00002512-200421100-00001

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