Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease |
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| Authors: | Marta Pera Delfina Larrea Cristina Guardia‐Laguarta Jorge Montesinos Kevin R Velasco Rishi R Agrawal Yimeng Xu Robin B Chan Gilbert Di Paolo Mark F Mehler Geoffrey S Perumal Frank P Macaluso Zachary Z Freyberg Rebeca Acin‐Perez Jose Antonio Enriquez Eric A Schon Estela Area‐Gomez |
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| Institution: | 1. Department of Neurology, Columbia University Medical Center, New York, NY, USA;2. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;3. Institute of Human Nutrition, Columbia University Medical Campus, New York, NY, USA;4. Departments of Neurology, Neuroscience, and Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA;5. Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, USA;6. Departments of Psychiatry and Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA;7. Cardiovascular Metabolism Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain;8. Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA |
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| 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. |
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| Keywords: | Alzheimer's disease C99
MAM
mitochondria and sphingolipids |
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