Maria Ankarcrona group

Mitochondrial dysfunction in Alzheimer Disease

Research focus

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. Our lab has for example revealed that amyloid-b peptide (Aβ) is imported into the mitochondria via the TOM (translocase of the outer membrane) complex (Hansson Petersen et al., 2008). Proper mitochondrial function and energy production is crucial for synaptic activity, thus mitochondrial failure may precede the cognitive decline observed in AD. In accordance, using new knock-in models of AD – the AppNL-F and AppNL-G-F, and combining transcriptomics, functional and imaging data we observed that mitochondrial impairment in hippocampus precedes Aβ deposition, neuroinflammation and synaptic alterations.

Currently, our lab has three main research projects:

Role of mitochondria-ER contacts in synaptic activity and AD degeneration

Mitochondria-associated ER membranes (MAM) is a specialized, lipid-raft like region of ER where many important cellular processes (e.g., calcium (Ca2+) transfer, autophagy, metabolism of glucose, phospholipids, fatty acids, and cholesterol) are regulated. MERCS are formed when approximately 20% of the mitochondrial surface is closely opposed to MAM (10 to 30 nm distance). Our group has discovered that TOM70 operates as an ER–Ca2+ regulator, facilitating Ca2+ shuttling at MERCS, and influencing bioenergetics, cell proliferation, and autophagy (Filadi et al., 2018, Leal et al., 2020). More recently, we have also shown that MERCS regulate vesicle release (Dentoni et al., 2022). Interestingly, all these processes are altered in AD and, therefore, we believe that increased ER to mitochondria apposition as a key factor in AD pathogenesis. Our latest strategy is focus on the role of MERCS in microglia for regulation inflammasome activation and its influence on synaptic activity.

Flavonoids as stabilizers of mitochondrial function in neurodegeneration

We have recently established a cell-based screen and identified flavonoids as mitochondrial enhancers (Naia et al., 2021). Applying gene editing strategies, we are now identifying molecular targets of these small compounds. Moreover, using AD knock-in models we are generating proof-of-concept data supporting these drugs as disease-modifying therapy for AD and other neurodegenerative disorders.

Mechanisms regulating neuron-astrocyte mitochondrial transfer

Recent evidence suggest that mitochondria can be transferred between neuronal cells, a phenomenon that may offer novel opportunities to protect, repair and report on brain disorders. This project aims to study mechanisms regulating mitochondrial transfer between neurons and astrocytes (e.g., extracellular vesicles, tunnelling nanotubes) that can offer a better understanding of AD-related synaptic degeneration.


Group members

Luana Naia

Assistant professor

Ming Ho Choi

Postdoctoral researcher

Maria Lindskog

(affiliated to research)

Selected publications

Mitochondria-Endoplasmic Reticulum Interplay Regulates Exo-Cytosis in Human Neuroblastoma Cells.
Dentoni G, Naia L, Ankarcrona M
Cells 2022 Feb;11(3):

Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease.
Dentoni G, Naia L, Portal B, Leal NS, Nilsson P, Lindskog M, Ankarcrona M
J Alzheimers Dis 2022 ;90(2):565-583

Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling.
Naia L, Pinho CM, Dentoni G, Liu J, Leal NS, Ferreira DMS, Schreiner B, Filadi R, Fão L, Connolly NMC, Forsell P, Nordvall G, Shimozawa M, Greotti E, Basso E, Theurey P, Gioran A, Joselin A, Arsenian-Henriksson M, Nilsson P, Rego AC, Ruas JL, Park D, Bano D, Pizzo P, Prehn JHM, Ankarcrona M
BMC Biol 2021 Mar;19(1):57

Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons.
Theurey P, Connolly NMC, Fortunati I, Basso E, Lauwen S, Ferrante C, Moreira Pinho C, Joselin A, Gioran A, Bano D, Park DS, Ankarcrona M, Pizzo P, Prehn JHM
Aging Cell 2019 Jun;18(3):e12924

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients.
Leal NS, Dentoni G, Schreiner B, Kämäräinen OP, Partanen N, Herukka SK, Koivisto AM, Hiltunen M, Rauramaa T, Leinonen V, Ankarcrona M
Acta Neuropathol Commun 2018 Oct;6(1):102

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, Wiehager B, Cieri D, Calì T, Pizzo P, Ankarcrona M
Curr Biol 2018 Feb;28(3):369-382.e6

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

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

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

The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.
Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M
Proc Natl Acad Sci U S A 2008 Sep;105(35):13145-50


Giacomo Dentoni, 2021: Mitochondria-Endoplasmic Reticulum contacts in neuronal cells: From physiology to therapeutics

Nuno Santos Leal, 2019: The interplay between mitochondria-endoplasmic reticulum contacts and Alzheimer’s disease

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


Karolinska Institutet 
Department of Neurobiology, Care Sciences and Society
Division of Neurogeriatrics
BioClinicum J9:20
Visionsgatan 4
171 64 Solna


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