The large hydrophilic loop of presenilin 1 is important for regulating gamma-secretase complex assembly and dictating the amyloid beta peptide (Abeta) Profile without affecting Notch processing.

The Journal of Biological Chemistry
Johanna WanngrenHelena Karlström

Abstract

Gamma-secretase is an enzyme complex that mediates both Notch signaling and beta-amyloid precursor protein (APP) processing, resulting in the generation of Notch intracellular domain, APP intracellular domain, and the amyloid beta peptide (Abeta), the latter playing a central role in Alzheimer disease (AD). By a hitherto undefined mechanism, the activity of gamma-secretase gives rise to Abeta peptides of different lengths, where Abeta42 is considered to play a particular role in AD. In this study we have examined the role of the large hydrophilic loop (amino acids 320-374, encoded by exon 10) of presenilin 1 (PS1), the catalytic subunit of gamma-secretase, for gamma-secretase complex formation and activity on Notch and APP processing. Deletion of exon 10 resulted in impaired PS1 endoproteolysis, gamma-secretase complex formation, and had a differential effect on Abeta-peptide production. Although the production of Abeta38, Abeta39, and Abeta40 was severely impaired, the effect on Abeta42 was affected to a lesser extent, implying that the production of the AD-related Abeta42 peptide is separate from the production of the Abeta38, Abeta39, and Abeta40 peptides. Interestingly, formation of the intracellular domains of both APP and...Continue Reading

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Citations

Jul 20, 2011·The Journal of Biological Chemistry·Annelie PamrénHelena Karlström
Jul 3, 2015·Molecular Medicine Reports·Zeng-Zhang ZhengHong-Sheng Song
Aug 14, 2010·Neurochemistry International·Homira BehbahaniMaria Ankarcrona
Apr 21, 2009·FEBS Letters·Yoshihiro SuzukiToshiyuki Nakagawa
Nov 9, 2010·Journal of Cellular and Molecular Medicine·Louise HedskogMaria Ankarcrona

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