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Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

EMBO J. 2012 Nov 5;31(21):4106-23. doi: 10.1038/emboj.2012.202. Epub 2012 Aug 14.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Membrane Microdomains / metabolism
  • Membrane Microdomains / pathology*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / pathology*
  • Presenilin-1 / antagonists & inhibitors
  • Presenilin-1 / physiology*
  • Presenilin-2 / antagonists & inhibitors
  • Presenilin-2 / physiology*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subcellular Fractions

Substances

  • Presenilin-1
  • Presenilin-2
  • RNA, Messenger
  • RNA, Small Interfering