Dimitrov M, Alattia JR, Lemmin T, Lehal R, Fligier A, Houacine J, Hussain I, Radtke F, Dal Peraro M, Beher D, Fraering PC. Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun. 2013;4:2246. PubMed.
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The finding of a decrease in the AICD 49-99/50-99 ratio due to APP mutations near the γ- or ε-site is intriguing, and may partly answer why these mutations increase the Aβ 42/40 ratio if the step-wise cleavage hypothesis is correct.
That GSMs have no effect on the epsilon cleavage is a common knowledge. GSM-1 has been proposed to bind to presenilin rather than APP, resulting in the conformation change in the pore of γ -secretase, which may explain the present finding that GSM-1 works regardless of having FAD mutations in APP. I am curious whether these findings will be reproduced in the cellular or even in vivo studies because a cell-free system with exogenous APP is somewhat artificial and sometimes shows different phenotypes from that observed in the cellular system.
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