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Review
. 2007 Feb;8(2):136-40.
doi: 10.1038/sj.embor.7400896.

When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease

Michael S Wolfe  1
Affiliations
Review

When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease

Michael S Wolfe. EMBO Rep. 2007 Feb.

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 gamma-secretase complex, which is responsible for producing the amyloid beta-peptide (Abeta) 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 Abeta 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 Abeta.

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Figures

Figure 1
Figure 1
Ihara model of processive proteolysis of the amyloid precursor protein transmembrane domain by γ-secretase, beginning at the ε-cleavage site and cleaving every three residues. This model explains how reduction of proteolytic function owing to presenilin mutations might lower amyloid β-peptide (Aβ) production but increase the ratio of Aβ42 to Aβ40. Longer forms of Aβ, with more of the hydrophobic transmembrane domain, might be more likely to be retained in the active site of the protease, whereas the shorter forms are more likely to be released. Less catalytically efficient γ-secretase complexes would allow more time for the release of longer Aβ peptides. In addition, Alzheimer disease-causing presenilin mutations shift the initial ε-cleavage site to produce more Aβ48, which would lead to Aβ42. AICD, APP intracellular domain; APP, amyloid precursor protein.
None
Michael S. Wolfe
See this image and copyright information in PMC

References

    1. Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK (2004) PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23: 2586–2596 - PMC - PubMed
    1. Beglopoulos V, Shen J (2006) Regulation of CRE-dependent transcription by presenilins: prospects for therapy of Alzheimer's disease. Trends Pharmacol Sci 27: 33–40 - PubMed
    1. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B (2006) Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 96: 732–742 - PubMed
    1. Borchelt DR et al. (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005–1013 - PubMed
    1. Citron M et al. (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3: 67–72 - PubMed

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