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Séminaire impromptu - Maria AnkarcronaER-mitochondria interplay in Alzheimer’s disease

Abstract :

 Contact points between mitochondria and the endoplasmic reticulum (ER) function as signaling hubs in the cell.
Ca2+-transfer as well as lipid biosynthesis and trafficking take place at these specialized cholesterol rich subdomains of the ER membrane, also referred to as mitochondria associated ER membranes (MAM), which are in close proximity (20-30 nm) to the mitochondrial outer membrane.

We and others have previously shown that the ER-mitochondria interplay is altered in Alzheimer´s disease (AD) and related models (Zampese et al 2011, Filadi et al 2016, Area-Gomez et 2012; Hedskog et al 2013). AD-models show increased Ca2+transfer from ER to mitochondria and upregulation of lipid synthesis. In a following study we measured Ab generation from membrane preparations of subcellular fractions prepared from mouse brain. Interestingly, we found that significant amounts of Ab were generated from the MAM fraction suggesting that Ab is produced in the vicinity of mitochondria (Schreiner et al, JAD 2015). We have also demonstrated that modulation of ER-mitochondria contact affects Ab production. siRNA knock-down of Mitofusin-2  resulted in increased contact between the two membranes and increased Ca2+transfer from ER to mitochondria.

ELISA measurements of both intra- and extracellular Ab levels showed that increased contact between ER and mitochondria at MAM decrease the production of Ab. In summary, these studies show that Mitofusin-2 is a negative regulator of ER-mitochondria contact and that increased contact leads to decreased Ab production due to impaired function of the g-secretase complex (Leal et al, JCMM 2016). In a recently published study we have analyzed ER-mitochondria contacts in human brain biopsies and find positive correlations between the number of contacts and age as well as ventricular CSF Ab-levels (Leal et al 2018).
Moreover the translocase of the outer mitochondrial membrane 70 (TOM70) was identified as a potential target for modulation of functional aspects of MAM as knock-down of TOM70 results in decreased Ca2+-transfer from ER to mitochondria (Filadi et al, 2018).  In summary, our data suggest that the ER-mitochondria interplay is a ‘hot spot’ for several cellular processes impaired in AD including Ca2+-homeostasis, mitochondrial functions and autophagy.

Selected publications

Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences Bano D, Ankarcrona M Neuroscience letters 2018;663():79-85

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 and differentiation 2018;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 Journal of molecular biology 2018;430(3):348-362

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 Current biology : CB 2018;28(3):369-382.e6

Scientific focus :

I am Professor of Experimental Neurogeriatrics and study cellular mechanisms in Alzheimer's disease. I am the head of the Division of Neurogeriatrics, NVS and one of three leaders of the Center for Alzheimer Research, KI. During the 2012-2017 I was a director of doctoral education at NVS, and at present I am faculty representative in the Board of Doctoral Education (FUS). This is a very interesting, stimulating and important mission. I have taken part in the design of the electronic individual study plan, and I am a representative of the KID steering committee, where we partially reformed the review and decision-making process. Through my long involvement in doctoral education at KI, I have gained extensive experience in board and committee work. Driving issues that I am passionate about and being a part of developing KI are both interesting and fun.