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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 ?1 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 ?-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.

SUBMITTER: Hedskog L 

PROVIDER: S-EPMC3651455 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.

Hedskog Louise L   Pinho Catarina Moreira CM   Filadi Riccardo R   Rönnbäck Annica A   Hertwig Laura L   Wiehager Birgitta B   Larssen Pia P   Gellhaar Sandra S   Sandebring Anna A   Westerlund Marie M   Graff Caroline C   Winblad Bengt B   Galter Dagmar D   Behbahani Homira H   Pizzo Paola P   Glaser Elzbieta E   Ankarcrona Maria M  

Proceedings of the National Academy of Sciences of the United States of America 20130425 19


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 containin  ...[more]

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