Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. (10th October 2017)

• Record Type: Journal Article
• 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‐Gomez, Estela
• Is Part Of: EMBO journal. Volume 36:Number 22(2017)
• Page Start: 3356
• Page End: 3371
• Publication Date: 2017-10-10
• Subjects: Alzheimer's disease -- C99 -- MAM -- mitochondria and sphingolipids; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796797
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: In animal and cellular models of Alzheimer disease (AD) and in fibroblasts from AD patients, APP‐C99 levels are increased in mitochondria‐associated endoplasmic reticulum membrane (ER‐MAM) regions, resulting in perturbed lipid homeostasis and mitochondrial dysfunction. Cells from AD patients and AD animal and cellular models show significant increases in C99 levels in ER‐MAM regions. The increased presence of C99 in MAM causes the loss of regulation of MAM functionality and greater apposition between ER and mitochondria. Among the functions located at MAM affected by the higher concentration of C99, sphingolipid homeostasis is significantly altered, resulting in the upregulation of sphingomyelin hydrolysis and the subsequent increases in ceramide. These increases in ceramide at ER‐MAM domains alter mitochondrial functionality. These results can help explain the cause of lipid and mitochondrial abnormalities in AD, and support a model in which increased C99 plays an early role in AD pathogenesis, via altered MAM function. Abstract : In animal and cellular models of Alzheimer disease (AD) and in fibroblasts from AD patients, APP‐C99 levels are increased in mitochondria‐associated endoplasmic reticulum membrane (ER‐MAM) regions, resulting in perturbed lipid homeostasis and mitochondrial dysfunction.