Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. re2
[DOI: 10.1126/sageke.2006.10.re2]


Targeting the Role of the Endosome in the Pathophysiology of Alzheimer's Disease: A Strategy for Treatment

Barbara A. Tate, and Paul M. Mathews

The authors are at CNS Discovery, Global Research and Development, Pfizer Inc., Groton, CT 06234, USA (B.A.T.) and the Department of Psychiatry at the New York University School of Medicine, Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA (P.M.M). E-mail: barbara.tate{at} (B.A.T.), mathews{at} (P.M.M.)

Key Words: Alzheimer's disease • amyloid • APP • endosome • Down syndrome • Niemann-Pick • secretase • cholesterol • drug discovery

Abstract: Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, and often critically regulate the cell-surface availability of receptors and other plasma membrane proteins in many different cell types. Neurons are no exception, being dependent on endosomal function for housekeeping and synaptic events. Growing evidence suggests a link between neuronal endosomal function and Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons in AD brains, and endocytic compartments are one likely site for the production of the pathogenic beta-amyloid peptide (Abeta), which accumulates within the brain during the disease and is generated by proteolytic processing of the amyloid precursor protein (APP). The enzymes and events involved in APP processing are appealing targets for therapeutic agents aimed at slowing or reversing the pathogenesis of AD. The neuronal endosome may well prove to be the intracellular site of action for inhibitors of beta-amyloidogenic APP processing. We present here the view that knowledge of the endosomal system in the disease can guide drug discovery of AD therapeutic agents.

Citation: B. A. Tate, P. M. Mathews, Targeting the Role of the Endosome in the Pathophysiology of Alzheimer's Disease: A Strategy for Treatment. Sci. Aging Knowl. Environ. 2006 (10), re2 (2006).

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