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EMBO reports 8, 2, 136–140 (2007)
doi:10.1038/sj.embor.7400896
When loss is gain: reduced presenilin proteolytic function leads to increased A 42/A40. Talking Point on the role of presenilin mutations in Alzheimer disease
Michael S Wolfe
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Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institute of Medicine 754, Boston, Massachusetts 02115, USA
Tel: +1 617 525 5511; Fax: +1 617 525 5511;
e-mail: mwolfe@rics.bwh.harvard.edu
Received 21 August 2006; Accepted 14 November 2006.
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Abstract
More than 100 missense mutations in presenilin 1 and 2 are associated with early-onset dominant Alzheimer disease. These proteins span the membrane several times and are ostensibly the catalytic component of the  -secretase complex, which is responsible for producing the amyloid -peptide (A) that deposits in the Alzheimer brain. A common outcome of Alzheimer-associated presenilin mutations is an increase in the ratio of the more aggregation-prone 42-residue form of A to the 40-residue variant, which is often referred to as a presenilin 'gain of function'. An apparent paradox is that most of these mutant presenilins have reduced proteolytic efficiency, which forms part of the counter argument that presenilin 'loss of function' can cause the neuronal dysfunction and death that lead to the disease. In this review, a unifying hypothesis is presented that puts forward a biochemical mechanism by which slower less-efficient forms of the protease can result in a greater proportion of 42-residue A.
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