Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.
EMBO J
; 31(21): 4106-23, 2012 Nov 05.
Article
in En
| MEDLINE
| ID: mdl-22892566
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Membrane Microdomains
/
Embryo, Mammalian
/
Mitochondrial Membranes
/
Presenilin-1
/
Presenilin-2
/
Alzheimer Disease
/
Fibroblasts
/
Mitochondria
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO J
Year:
2012
Document type:
Article
Affiliation country:
United States