Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-08-02

AUTHORS

Mitko Dimitrov, Jean-René Alattia, Thomas Lemmin, Rajwinder Lehal, Andrzej Fligier, Jemila Houacine, Ishrut Hussain, Freddy Radtke, Matteo Dal Peraro, Dirk Beher, Patrick C. Fraering

ABSTRACT

Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical γ-secretase modulators affect the processing of APP by the γ-secretase complex and the production of the amyloid-beta peptide Aβ42, the accumulation of which is considered causative of Alzheimer’s disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer’s disease affect both γ- and ε-cleavage sites, by raising the Aβ42/40 ratio and inhibiting the production of AICD50–99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to γ-secretase modulators, which shift Aβ42 production towards the shorter Aβ38, but unequivocally spare the ε-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer’s disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its γ-site, modifying at the same time, the solvation of the ε-site. More... »

PAGES

2246

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms3246

DOI

http://dx.doi.org/10.1038/ncomms3246

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000823660

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23907250


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