Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models
Autor: | Catarina Moreira Pinho, Elzbieta Glaser, Pia Larssen, Annica Rönnbäck, Sandra Gellhaar, Anna Sandebring, Riccardo Filadi, Marie Westerlund, Paola Pizzo, Caroline Graff, Dagmar Galter, Bengt Winblad, Maria Ankarcrona, Homira Behbahani, Louise Hedskog, Birgitta Wiehager, Laura Hertwig |
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Jazyk: | angličtina |
Rok vydání: | 2013 |
Předmět: |
Amyloid
Cell Vesicular Transport Proteins CHO Cells Mitochondrion Endoplasmic Reticulum Hippocampus Mice Membrane Microdomains Alzheimer Disease Cell Line Tumor Cricetinae medicine Amyloid precursor protein Animals Humans Inositol 1 4 5-Trisphosphate Receptors Receptors sigma RNA Small Interfering Receptor Neurons Multidisciplinary biology Endoplasmic reticulum Brain Lipid metabolism Receptor Cross-Talk Biological Sciences medicine.disease Cell biology Mitochondria Disease Models Animal medicine.anatomical_structure Apoptosis Gene Knockdown Techniques Mutation biology.protein Calcium Alzheimer's disease Subcellular Fractions |
Popis: | 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. |
Databáze: | OpenAIRE |
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