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

• Marta Pera ^[1] ; Delfina Larrea ^[1] ; Cristina Guardia‐Laguarta ^[1] ; Jorge Montesinos ^[1] ; Kevin R Velasco ^[1] ; Rishi R Agrawal ^[5] ; Yimeng Xu ^[1] ; Robin B Chan ^[1] ; Gilbert Di Paolo ^[1] ; Mark F Mehler ^[2] ; Geoffrey S Perumal ^[2] ; Frank P Macaluso ^[2] ; Zachary Z Freyberg ^[3] ; Rebeca Acin‐Perez ^[4] ; Jose Antonio Enriquez ^[4] ; Eric A Schon ^[6] ; Estela Area‐Gomez ^[1]
  1. [1] Columbia University Medical Center

     Columbia University Medical Center

     Estados Unidos

     
  2. [2] Albert Einstein College of Medicine

     Albert Einstein College of Medicine

     Estados Unidos

     
  3. [3] University of Pittsburgh

     University of Pittsburgh

     City of Pittsburgh, Estados Unidos

     
  4. [4] Centro Nacional de Investigaciones Cardiovasculares Carlos III

     Centro Nacional de Investigaciones Cardiovasculares Carlos III

     Madrid, España

     
  5. [5] 3 Institute of Human Nutrition Columbia University Medical Campus New York NY USA
  6. [6] 1 Department of Neurology Columbia University Medical Center New York NY USA; 8 Department of Genetics and Development Columbia University Medical Center New York NY USA

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 22, 2017, págs. 3356-3371
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • 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.