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ApoE4 upregulates the activity of mitochondria‐associated ER membranes
Author(s) -
Tambini Marc D,
Pera Marta,
Kanter Ellen,
Yang Hua,
GuardiaLaguarta Cristina,
Holtzman David,
Sulzer David,
AreaGomez Estela,
Schon Eric A
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201540614
Subject(s) - mitochondrion , microbiology and biotechnology , membrane , chemistry , biology , biochemistry
In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease ( AD ) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum ( ER ) membranes ( MAM ), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media ( ACM ) model, we now show that ER –mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM . Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.