Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.
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.
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Estela
E
Area-Gomez
Maria
M
Del Carmen Lara Castillo
Marc D
MD
Tambini
Cristina
C
Guardia-Laguarta
Ad J C
AJ
de Groof
Moneek
M
Madra
Junichi
J
Ikenouchi
Masato
M
Umeda
Thomas D
TD
Bird
Stephen L
SL
Sturley
Eric A
EA
Schon
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D053766:Presenilin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions
D053764:Presenilin-1; D053766:Presenilin-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering