Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Dimitrov M,Alattia JR,Lemmin T,Lehal R,Fligier A,Houacine J,Hussain I,Radtke F,Dal Peraro M,Beher D,Fraering PC

doi

10.1038/ncomms3246

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

2246

issn

2041-1723

pii

ncomms3246

journal_volume

4

pub_type

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