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 Communjournal_title
Nature communicationsauthors
Dimitrov M,Alattia JR,Lemmin T,Lehal R,Fligier A,Houacine J,Hussain I,Radtke F,Dal Peraro M,Beher D,Fraering PCdoi
10.1038/ncomms3246subject
Has Abstractpub_date
2013-01-01 00:00:00pages
2246issn
2041-1723pii
ncomms3246journal_volume
4pub_type
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