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Has the Smoking Gun of Alzheimer's Disease Been Identified?

Evidence has been mounting that Alzheimer's disease (AD) is proximally caused by the Aß peptide, the degradation product of amyloid precursor protein (APP), which is a normally expressed cell surface protein. It has long been known that the density of plaques, which are composed of Aß peptides, correlates with cognitive impairment and cortical neurosynaptic deficits. However, mutations in APP are an exceedingly rare cause of AD; mutations of the genes encoding presenilin 1 and 2 are much more frequent and appear to preferentially generate Aß_1-42, a form that produces more plaques. Recently, research focused on the enzymes that clip out the amyloidogenic peptide Aß from APP and identified the beta and gamma secretases that cleave APP at the amino and carboxy termini.

This new study provides compelling evidence that the active site for gamma secretase is contained within the presenilin, the mutations of which are responsible for early-onset AD. Researchers used photoaffinity labeling of the presenilin to show that specific inhibitors of gamma secretase prevented the generation of Aß.

Comment: Identifying the final common pathway for the pathophysiology of Alzheimer's disease is extremely important for developing effective therapies. The linkage of presenilin gene mutations to the disposition of APP and the generation of Aß_1-42 is an important advance. However, the pharmacology is not trivial: The presenilin protease is an unusual membrane-embedded enzyme that may prove difficult to target. Nevertheless, this discovery offers hope for pharmacologic preventive interventions, much like the statins in atherosclerosis. - J Coyle

Published in Journal Watch Psychiatry July 18, 2000

Citation(s):

Li YM et al. Photoactivated (gamma)-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000 Jun 8 405 689-693.

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