Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria

Am J Pathol. 2009 Nov;175(5):1810-6. doi: 10.2353/ajpath.2009.090219. Epub 2009 Oct 15.


Presenilin-1 (PS1) and -2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, gamma-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Cells, Cultured
  • Coenzyme A Ligases / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Humans
  • Intracellular Membranes / metabolism*
  • Intracellular Membranes / ultrastructure
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism*
  • Rats
  • Subcellular Fractions / metabolism


  • Presenilin-1
  • Presenilin-2
  • Amyloid Precursor Protein Secretases
  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase