title: Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.
abstract: It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)Swe/Lon mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Hedskog
authors.forename: Catarina Moreira
authors.initials: CM
authors.lastname: Pinho
authors.forename: Riccardo
authors.initials: R
authors.lastname: Filadi
authors.forename: Annica
authors.initials: A
authors.lastname: Rönnbäck
authors.forename: Laura
authors.initials: L
authors.lastname: Hertwig
authors.forename: Birgitta
authors.initials: B
authors.lastname: Wiehager
authors.forename: Pia
authors.initials: P
authors.lastname: Larssen
authors.forename: Sandra
authors.initials: S
authors.lastname: Gellhaar
authors.forename: Anna
authors.initials: A
authors.lastname: Sandebring
authors.forename: Marie
authors.initials: M
authors.lastname: Westerlund
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Homira
authors.initials: H
authors.lastname: Behbahani
authors.forename: Paola
authors.initials: P
authors.lastname: Pizzo
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
authors.forename: Maria
authors.initials: M
authors.lastname: Ankarcrona
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020239:Receptor Cross-Talk; D017480:Receptors, sigma / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000682:Amyloid; D002118:Calcium; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D033921:Vesicular Transport Proteins; D000097605:Sigma-1 Receptor; C499638:PACS2 protein, human
keywords: AD mouse models; hippocampal neurons; human cortical brain tissue