Maria Ankarcrona Group
Mitochondria 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 in these processes.
It is well established that brain metabolism and mitochondrial function is 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. We and others have detected Aβ in mitochondria from AD brain and AD mouse models and in vitro experiments revealed impairment of mitochondrial functions in cells exposed to Aβ. Our lab has also reported that Aβ is imported into the mitochondria via the TOM (translocase of the outer membrane) complex (Hansson Petersen et al., 2008). We are now expanding these studies to investigate the role of mitochondria associated ER-membranes (MAM) in eg Aβ production, mitochondrial function and regulation of cell death mechanisms.
MAM is a specialized, lipid-raft like region of ER where many important cellular processes (eg calcium transfer, apoptosis, 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. In two recent studies have investigated the modulation of the MAM region and ER-mitochondria contact points in AD brain, AD mouse models and primary hippocampal neurons exposed to oligomeric Aβ (Hedskog et al 2013) and the generation of Aβ at MAM (Schreiner et al 2014). Methods used include confocal microscopy, proximity ligation assay, calcium measurements, Western blot, immunohistochemistry, immunocytochemistry, subcellular fractionation and cell death assays.
Our research group is also part of the CeBioND (Cellular Bioenergetics in Neurodegenerative Diseases) consortium supported by JPND/VR with Dr Maria Ankarcrona as coordinator. The aim of the CeBioND is to elucidate common and distinct disease mechanisms in AD, Parkinson’s disease and Huntington’s disease focusing on pathways regulating mitochondrial functions and cell bioenergetics. In addition, CeBioND employs computational modelling frameworks and a high-throughput screen approach developed by the partners to identify drug candidates and therapeutic targets.
|Maria Ankarcrona||Associate professor|
|Birgitta Wiehager||Lab assistant|
|Nuno Leal||PhD student|
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
Amyloid-β Peptides are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes. Schreiner B, Hedskog L, Wiehager B, Ankarcrona M. J Alzheimers Dis. 2014 Aug 5. [Epub ahead of print]
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, Larssen P, Gellhaar S, Sandebring A, Westerlund M, Graff C, Winblad B, Galter D, Behbahani H, Pizzo P, Glaser E, Ankarcrona M. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7916-21
Biochemical studies of poly-T variants in the Alzheimer's disease associated TOMM40 gene.
J. Alzheimers Dis. 2012 ;31(3):527-36
Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein.
FASEB J. 2011 Jan;25(1):78-88
Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease.
FASEB J. 2011 Apr;25(4):1345-52
γ-Secretase complexes containing caspase-cleaved presenilin-1 increase intracellular Aβ(42) /Aβ(40) ratio.
J. Cell. Mol. Med. 2011 Oct;15(10):2150-63
Association of Omi/HtrA2 with γ-secretase in mitochondria.
Neurochem. Int. 2010 Nov;57(6):668-75
Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death.
J. Alzheimers Dis. 2010 ;21(2):389-402
The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.
Proc. Natl. Acad. Sci. U.S.A. 2008 Sep;105(35):13145-50
Department of Neurobiology, Care Sciences and Society
Center for Alzheimer Research
Division of Neurogeriatrics
Novum, Floor 5, Blickagången 6
SE-141 57 Stockholm