Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/6492
Título
Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease
Autor(es)
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 CNIC | Enriquez, Jose Antonio CNIC | Schon, Eric A. | Area-Gómez, Estela
Fecha de publicación
2017
Cita
EMBO J. 2017; 36(22):3356-3371
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
Palabras clave
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
Versión en línea
DOI
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