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PNAS 98 (20): 11039-11041

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper


Presenilin, Notch, and the genesis and treatment of Alzheimer's disease

Dennis J. Selkoe*

Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115

Abstract: Elucidation of the proteolytic processing of the amyloid β-protein precursor (APP) has revealed that one of the two proteases ({gamma}-secretase) that cleave APP to release amyloid β-protein (Aβ) is likely to be presenilin. Presenilin also mediates the {gamma}-secretase-like cleavage of Notch receptors to enable signaling by their cytoplasmic domains. Therefore, APP and Notch may be the first identified substrates of a unique intramembranous aspartyl protease that has presenilin as its active-site component. In view of the evidence for a central role of cerebral build-up of Aβ in the pathogenesis of Alzheimer's disease, this disorder appears to have arisen in the human population as a late-life consequence of the conservation of a critical developmental pathway.

* E-mail: selkoe{at}

This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

{dagger} Molinoff, P. B., Felsenstein, K. M., Smith, D. W. & Barten, D. M. (2000) Aβ modulation: The next generation of AD therapeutics (World Alzheimer's Congress 2000, Washington, DC, July 9–13, 2000), abstr. no. 615.

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