Maria Ankarcrona group
Mitochondrial dysfunction in Alzheimer Disease
Our main objective is to understand the mechanisms whereby cells degenerate in Alzheimer disease (AD). Our research is focused on the role of mitochondria and organelle interplay in these processes.
It is well established that brain metabolism and mitochondrial functions are impaired in AD. Proper mitochondrial function and energy production is crucial for synaptic activity, thus mitochondrial failure may precede the cognitive decline observed in AD. One possible explanation to mitochondrial dysfunction in AD brain is the accumulation of amyloid β-peptide (Aβ) in mitochondria. Our lab has for example revealed that Aβ is imported into the mitochondria via the TOM (translocase of the outer membrane) complex (Hansson Petersen et al., 2008). Recently we have established a cell-based assay for high-through put screening of compounds stabilizing mitochondrial function.
In other projects we are investigating the role of mitochondria associated membranes (MAM) in eg Aβ production, mitochondrial function, synaptic function and autophagy. MAM is a specialized, lipid-raft like region of ER where many important cellular processes (eg calcium transfer, apoptosis, autophagy, metabolism of glucose, phospholipids, fatty acids and cholesterol) are regulated. Interestingly, all these processes are altered in AD. At MAM the ER membrane and the outer mitochondrial membrane are in close proximity (20-30 nm) and a connected via protein scaffolds. We have recently shown that TOM70 is present in MAM where it regulates calcium transfer between ER and mitochondria.
Methods used in the lab include confocal microscopy, electron microscopy, proximity ligation assay, calcium measurements, Western blot, immunohistochemistry, immunocytochemistry, subcellular fractionation and cell death assays.
TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer.
Filadi R, Leal NS, Schreiner B, Rossi A, Dentoni G, Pinho CM, et al
Curr Biol 2018 02;28(3):369-382.e6
Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin.
Teixeira PF, Masuyer G, Pinho CM, Branca RMM, Kmiec B, Wallin C, et al
J Mol Biol 2018 02;430(3):348-362
Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.
Connolly NMC, Theurey P, Adam-Vizi V, Bazan NG, Bernardi P, Bolaños JP, et al
Cell Death Differ 2018 03;25(3):542-572
Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences.
Bano D, Ankarcrona M
Neurosci Lett 2018 01;663():79-85
Isolation of Mitochondria-Associated Membranes (MAM) from Mouse Brain Tissue.
Schreiner B, Ankarcrona M
Methods Mol Biol 2017 ;1567():53-68
Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production.
Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlström H, et al
J Cell Mol Med 2016 09;20(9):1686-95
Amyloid-β peptides are generated in mitochondria-associated endoplasmic reticulum membranes.
Schreiner B, Hedskog L, Wiehager B, Ankarcrona M
J Alzheimers Dis 2015 ;43(2):369-74
Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.
Hedskog L, Pinho CM, Filadi R, Rönnbäck A, Hertwig L, Wiehager B, et al
Proc Natl Acad Sci U S A 2013 May;110(19):7916-21
Louise Hedskog, 2012: Mitochondria in Alzheimer disease: Regulatory mechanisms and cell death
Camilla Hansson Petersen, 2009: Alzheimer disease associated Abeta and gamma-secretase: Mitochondrial localization and involvement in cell death
Alexandra Selivanova, 2007: Intracellular dynamics of Alzheimer Disease-related proteins
Bogdan Popescu, 2004: Cell death and signal transduction pathways in Alzheimers disease: The role of presenilin-1
Maria Ankarcrona, 1996: Mechanisms of apoptosis in secretory and neuronal cells : role of oxidative stress and calcium overload
Department of Neurobiology, Care Sciences and Society
Center for Alzheimer Research
Division of Neurogeriatrics
Novum, Floor 5, Blickagången 6
SE-141 57 Stockholm