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

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

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3356-3371
Number of pages16
JournalEMBO Journal
Volume36
Issue number22
DOIs
StatePublished - Nov 15 2017

Keywords

  • Alzheimer's disease
  • C99
  • MAM
  • mitochondria and sphingolipids

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease'. Together they form a unique fingerprint.

  • Cite this

    Pera, M., Larrea, D., Guardia-Laguarta, C., Montesinos, J., Velasco, K. R., Agrawal, R. R., Xu, Y., Chan, R. B., Di Paolo, G., Mehler, M. F., Perumal, G. S., Macaluso, F. P., Freyberg, Z. Z., Acin-Perez, R., Enriquez, J. A., Schon, E. A., & Area-Gomez, E. (2017). Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO Journal, 36(22), 3356-3371. https://doi.org/10.15252/embj.201796797