@article{f79cfd279ad34883aff0a4dd44bc754f,
title = "Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease",
abstract = "In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.",
keywords = "Alzheimer's disease, C99, MAM, mitochondria and sphingolipids",
author = "Marta Pera and Delfina Larrea and Cristina Guardia-Laguarta and Jorge Montesinos and Velasco, {Kevin R.} and Agrawal, {Rishi R.} and Yimeng Xu and Chan, {Robin B.} and {Di Paolo}, Gilbert and Mehler, {Mark F.} and Perumal, {Geoffrey S.} and Macaluso, {Frank P.} and Freyberg, {Zachary Z.} and Rebeca Acin-Perez and Enriquez, {Jose Antonio} and Schon, {Eric A.} and Estela Area-Gomez",
note = "Funding Information: (W911NF-12-1-9159 and W911F-15-1-0169), and the J. Willard and Alice S. Marriott Foundation (to E.A.S.); the U.S. National Institutes of Health (P01-HD080642 and P01-HD032062 to E.A.S.; NS071571 and HD071593 to M.F.M.; R01-NS056049 and P50-AG008702 to G.D.P.; 1S10OD016214-01A1 to G.S.P. and F.P.M, and K01-AG045335 to E.A.-G.), the Lucien Cot{\'e} Early Investigator Award in Clinical Genetics from the Parkinson{\textquoteright}s Disease Foundation (PDF-CEI-1364 and PDF-CEI-1240) to C.G.-L., and National Defense Science and Engineering Graduate Fellowship (FA9550-11-C-0028) to R.R.A. Funding Information: We thank Drs. Orian Shirihai and Marc Liesa (UCLA) for assistance with the Seahorse measurements, Dr. Huaxi Xu (Sanford Burnham Institute) for the APP-DKO MEFs and Dr. Mark Mattson (NIH) for the PS1 knock-in mice, Drs. Arancio and Teich for the APP-KO mice tissues used in these studies, Dr. Hua Yang (Columbia University) for mouse husbandry, and Drs. Marc Tambini, Ira Tabas, and Serge Przedborski for helpful comments. This work was supported by the Fundaci{\'o}n Alfonso Mart{\'i}n Escudero (to M.P.); the Alzheimer{\textquoteright}s Drug Discovery Foundation, the Ellison Medical Foundation, the Muscular Dystrophy Association, the U.S. Department of Defense Publisher Copyright: {\textcopyright} 2017 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2017",
month = nov,
day = "15",
doi = "10.15252/embj.201796797",
language = "English (US)",
volume = "36",
pages = "3356--3371",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "22",
}