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

Mitko Dimitrov, Jean-René Alattia, Thomas Lemmin, Rajwinder Lehal, Andrzej Fligier, Jemila Houacine, Ishrut Hussain, Freddy Radtke, Matteo Dal Peraro, Dirk Beher and Patrick C. Fraering ()
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Mitko Dimitrov: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Jean-René Alattia: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Thomas Lemmin: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Rajwinder Lehal: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Andrzej Fligier: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Jemila Houacine: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Ishrut Hussain: Global Research and Early Development, Merck Serono SA
Freddy Radtke: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Matteo Dal Peraro: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Dirk Beher: Global Research and Early Development, Merck Serono SA
Patrick C. Fraering: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3246

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