Mitochondrial dysfunction in Alzheimer Disease – Maria Ankarcrona's research group

It is well established that brain metabolism and mitochondrial functions are impaired in Alzheimer´s disease (AD). Our group investigates how mitochondrial dysfunction and altered dynamics, particularly disrupted endoplasmic reticulum (ER)–mitochondria communication and mitochondria transfer, contributes to AD. Using both knock-in mouse models of AD (Naia et al., 2023) and human hippocampal organoids, we show that mitochondria are hyperactive in function and dynamics at early stages of the disease. This is associated with increased Ca²⁺ dysregulation and oxidative stress. The decline of mitochondrial function occurs concomitantly to the rise in neuroinflammation and synaptic alterations. Using cellular models, 3D brain organoids, and mouse systems, the group aims to identify molecules that enhance mitochondrial bioenergetics and to develop novel therapeutic strategies to slow disease progression.

Currently, our lab has three main research lines:

1. Role of mitochondria-ER contacts in inflammation and neurodegeneration in AD (PI. M Ankarcrona)

Mitochondria–endoplasmic reticulum contact sites (MERCS) host specialized protein complexes that regulate key cellular processes (e.g., calcium (Ca²⁺) transfer, autophagy, metabolism of glucose, phospholipids, fatty acids, and cholesterol). MERCS are formed when approximately 20% of the mitochondrial surface is closely apposed to ER (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 current strategy focuses on defining the role of microglial mitochondria–ER contact sites (MERCS) in regulating inflammasome activation. Using microglia derived from an AD mouse model, we recently identified structural and functional alterations of MERCS. Notably, genetic modulation of microglial MERCS attenuates inflammasome activation and reduces inflammatory cytokine release, underscoring MERCS as a potential contributor to AD pathogenesis.

2. Flavonoids as stabilisers of mitochondrial function in neurodegeneration

(PI. M. Ankarcrona)

We have 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.

In collaboration with the University of Palermo we are investigating the protective effect of flavonoids on cognitive disturbances induced in a high-fat diet rat model.

3. Mitochondrial Architecture, Signaling, and Transfer in AD (PI. L Naia)

Mitochondria are highly dynamic organelles: they constantly undergo fusion and fission, move throughout the cell, interact with other organelles, release mitochondria-derived vesicles (mitoEVs), and can be transferred between cells. Our team investigates how these mitochondrial dynamics in astrocytes—the most abundant glial cells in the brain—shape neuronal function and contribute to Alzheimer’s disease.

Our main research projects focus on:

(i)    astrocyte-to-neuron mitochondrial transfer;

(ii)   functional and proteomic characterization of mitoEVs across disease progression and their potential neuroprotective roles;

(iii)  development of advanced imaging analysis pipelines and deep-learning models to study mitochondrial architecture, dynamics and function.

Detailed information about each project is available here: Luana Naia.

Address

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

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