Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

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 a...

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Authors: Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina; Montesinos, Jorge; Velasco, Kevin R.; Agrawal, Rishi R; Xu, Yimeng; Chan, Robin B.; Di Paolo, Gilbert; Mehler, Mark F.; Perumal, Geoffrey S.; Macaluso, Frank P.; Freyberg, Zachary Z.; Acin-Perez, Rebeca; Enriquez, Jose Antonio; Schon, Eric A.; Area-Gómez, Estela
Format: Article
Publication date:2017
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/6492
Online Access:http://hdl.handle.net/20.500.12105/6492
Access Level:Open access
Keyword: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
Summary: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.

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