title: ApoE4 upregulates the activity of mitochondria-associated ER membranes.
abstract: 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.
authors.affiliation: Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Tambini
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Pera
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kanter
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders Knight Alzheimer's Disease Research Center Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: David
authors.initials: D
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA eas3@columbia.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000096:biosynthesis; D017077:Culture Media, Conditioned / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010743:Phospholipids / Q000096:biosynthesis; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D053327:Apolipoprotein E4; D002788:Cholesterol Esters; D017077:Culture Media, Conditioned; D008074:Lipoproteins; D010743:Phospholipids; D002784:Cholesterol
keywords: ApoE; MAM; cholesterol; cholesteryl esters; endoplasmic reticulum; lipoproteins; mitochondria; phospholipids