Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

Estela Area-Gomez, Maria Del Carmen Lara Castillo, Marc D. Tambini, Cristina Guardia-Laguarta, Ad J C De Groof, Moneek Madra, Junichi Ikenouchi, Masato Umeda, Thomas D. Bird, Stephen L. Sturley, Eric A. Schon

Research output: Contribution to journalArticle

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Abstract

Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by γ-secretase, via an unknown mechanism. We recently showed that presenilin-1 and-2, the catalytic components of γ-secretase, and γ-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and γ-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD.

Original languageEnglish
Pages (from-to)4106-4123
Number of pages18
JournalEMBO Journal
Volume31
Issue number21
DOIs
Publication statusPublished - Oct 31 2012

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Mitochondria
Amyloid Precursor Protein Secretases
Endoplasmic Reticulum
Alzheimer Disease
Membranes
Presenilins
Presenilin-2
Presenilin-1
Intracellular Membranes
Amyloid beta-Protein Precursor
Cholesterol Esters
Fibroblasts
Processing
Lipid Metabolism
Organelles
Detergents
Phospholipids
Homeostasis
Communication
Calcium

All Science Journal Classification (ASJC) codes

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

Cite this

Area-Gomez, E., Del Carmen Lara Castillo, M., Tambini, M. D., Guardia-Laguarta, C., De Groof, A. J. C., Madra, M., ... Schon, E. A. (2012). Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO Journal, 31(21), 4106-4123. https://doi.org/10.1038/emboj.2012.202

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. / Area-Gomez, Estela; Del Carmen Lara Castillo, Maria; Tambini, Marc D.; Guardia-Laguarta, Cristina; De Groof, Ad J C; Madra, Moneek; Ikenouchi, Junichi; Umeda, Masato; Bird, Thomas D.; Sturley, Stephen L.; Schon, Eric A.

In: EMBO Journal, Vol. 31, No. 21, 31.10.2012, p. 4106-4123.

Research output: Contribution to journalArticle

Area-Gomez, E, Del Carmen Lara Castillo, M, Tambini, MD, Guardia-Laguarta, C, De Groof, AJC, Madra, M, Ikenouchi, J, Umeda, M, Bird, TD, Sturley, SL & Schon, EA 2012, 'Upregulated function of mitochondria-associated ER membranes in Alzheimer disease', EMBO Journal, vol. 31, no. 21, pp. 4106-4123. https://doi.org/10.1038/emboj.2012.202
Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, De Groof AJC, Madra M et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO Journal. 2012 Oct 31;31(21):4106-4123. https://doi.org/10.1038/emboj.2012.202
Area-Gomez, Estela ; Del Carmen Lara Castillo, Maria ; Tambini, Marc D. ; Guardia-Laguarta, Cristina ; De Groof, Ad J C ; Madra, Moneek ; Ikenouchi, Junichi ; Umeda, Masato ; Bird, Thomas D. ; Sturley, Stephen L. ; Schon, Eric A. / Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. In: EMBO Journal. 2012 ; Vol. 31, No. 21. pp. 4106-4123.
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