Aberrant Amyloid Precursor Protein (APP) Processing in Hereditary Forms of Alzheimer Disease Caused by APP Familial Alzheimer Disease Mutations Can Be Rescued by Mutations in the APP GxxxG Motif (original) (raw)

2010, Journal of Biological Chemistry

The identification of hereditary familial Alzheimer disease (FAD) mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) corroborated the causative role of amyloid-␤ peptides with 42 amino acid residues (A␤42) in the pathogenesis of AD. Although most FAD mutations are known to increase A␤42 levels, mutations within the APP GxxxG motif are known to lower A␤42 levels by attenuating transmembrane sequence dimerization. Here, we show that aberrant A␤42 levels of FAD mutations can be rescued by GxxxG mutations. The combination of the APP-GxxxG mutation G33A with APP-FAD mutations yielded a constant 60% decrease of A␤42 levels and a concomitant 3-fold increase of A␤38 levels compared with the Gly 33 wild-type as determined by ELISA. In the presence of PS1-FAD mutations, the effects of G33A were attenuated, apparently attributable to a different mechanism of PS1-FAD mutants compared with APP-FAD mutants. Our results contribute to a general understanding of the mechanism how APP is processed by the ␥-secretase module and strongly emphasize the potential of the GxxxG motif in the prevention of sporadic AD as well as FAD. * This work was supported by the Alzheimer Forschung Initiative e.V. (to L.-M. M.), the Deutsche Forschungsgemeinschaft (MU901 (to G. M.), HI 1502/1-1 (to P. W. H.)), the SFB740, Kompetenznetz Degenerative Demenzen (Fö rderkennzeichen 01 GI 0723), and the Hans und Ilse Breuer Stiftung. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and additional references.

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