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

Research focus

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 App^NL-F and App^NL-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.

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