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oai:repisalud.isciii.es:20.500.12105/64922024-09-27T08:23:18Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Pera, Marta author Larrea, Delfina author Guardia-Laguarta, Cristina author Montesinos, Jorge author Velasco, Kevin R. author Agrawal, Rishi R author Xu, Yimeng author Chan, Robin B. author Di Paolo, Gilbert author Mehler, Mark F. author Perumal, Geoffrey S. author Macaluso, Frank P. author Freyberg, Zachary Z. author Acin-Perez, Rebeca author Enriquez, Jose Antonio author Schon, Eric A. author Area-Gómez, Estela author 2017 In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by beta-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by c-secretase to generate the beta-amyloid (Ab) found in senile plaques. In previous reports, we and others have shown that c-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 c-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. EMBO J. 2017; 36(22):3356-3371 10.15252/embj.201796797 1460-2075 0261-4189 EMBO Journal 29018038 http://hdl.handle.net/20.500.12105/6492 Alzheimer's disease C99 MAM Mitochondria and sphingolipids AMYLOID PRECURSOR PROTEIN C-TERMINAL FRAGMENT BETA-SECRETASE ACTIVITY ENDOPLASMIC-RETICULUM MOUSE MODEL OXIDATIVE STRESS TRANSGENIC MICE LIPID RAFTS A-BETA SYNAPTIC MITOCHONDRIA Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease