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Reactive astrocytes in neurodegenerative diseases

Les astrocytes réactifs dans les maladies neurodégénératives

Group leader: Carole Escartin​

Published on 2 June 2021
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  Carole Escartin







Reactive astrocytes

We study astrocytes, a type of brain glial cells that play key supporting roles for neurons. Under pathological conditions, such as neurodegenerative diseases, astrocytes become reactive. This is defined by morphological changes, but the functional consequences remain unclear (Ben Haim et al., Front. Cell. Neuro., 2015; Escartin et al., Glia, 2019). Given the importance of astrocytes for brain homeostasis, any change in their functions may have major effects on neurons. 

We develop molecular tools to modulate and monitor reactive astrocytes in situ, in order to better understand the roles of these complex cells.

1. Viral vectors to selectively modulate astrocyte reactivity in vivo
We identified the JAK2-STAT3 pathway as a key signaling pathway controlling the reactive state of astrocytes in neurodegenerative diseases (Ben Haim et al., J. Neurosci., 2015; Ceyzériat et al., Neuroscience, 2016; Ceyzériat et al., Acta Neuropathol. Com., 2018). We have developed viral vectors to target this pathway in astrocytes in vivo and to manipulate their reactive state. With these molecular tools, it is possible to:

  • Understand what reactive astrocytes do in the brain, using fluorescent-activated cell sorting of astrocytes, transcriptomics, electrophysiology, biochemical and histological analysis as well as behavioral assessment (part 2).
  • Assess whether reactive astrocytes can be monitored with non-invasive brain imaging techniques to serve as biomarkers for brain diseases (part 3).
  • Implement alternative therapeutic strategies for brain diseases by targeting specific populations of reactive astrocytes (part 4).
 
Reactive astrocytes overexpressing GFAP (red) in a mouse model of Alzheimer's disease. They display an accumulation
of STAT3 (green) in their nucleus (labeled in blue with DAPI). Ben Haim et al., J. Neurosci., 2015.

 

2. Molecular and functional changes in reactive astrocytes in vivo
Our earlier in vivo studies of reactive astrocytes induced by the cytokine CNTF, revealed significant changes in multiple astrocyte functions (Escartin et al. J. Neurosci, 2006; 2007; Seidel et al., Glia, 2015). Thanks to a FRC grant, we further showed that reactive astrocytes alter synaptic transmission and plasticity in the hippocampus (Ceyzériat et al., Acta Neuropathol. Com., 2018). Through grants from ANR and Fondation Maladies Rares, we are now exploring the molecular and functional heterogeneity of reactive astrocytes, and implement multi-omics analysis of reactive glial cells in brain diseases. 

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Virus-mediated expression of  SOCS3 in astrocytes inhibits the JAK-STAT3 pathway and normalizes astrocyte transcriptome  in an AD mouse model (APP),  as evidenced by RNAseq on acutely sorted astrocytes. 
Ceyzériat et al., Acta Neuropathol. Com., 2018. In collaboration with CNRGH, Evry


 3. Reactive astrocytes as biomarkers for pathological situations 
Reactive astrocytes appear under pathological conditions, and thus could be used as biomarkers for brain diseases. In collaboration with brain imaging teams in MIRCen, we showed that reactive astrocytes are detected by positron emission tomography (PET) with radiotracers for TSPO, a protein previously described as a reactive microglia marker (Lavisse et al. J. Neurosci., 2012).

TSPO-PET evidences reactive astrocytes in the rat brain (arrowhead in A), as confirmed by specific GFAP immunostaining 
of these cells (arrowhead in B). Lavisse et al. J. Neuroscience, 2012.

 

4. Reactive astrocytes as therapeutic targets for neurodegenerative diseases
Finally, through grants from ANR, LECMA/Vaincre Alzheimer, FRC and Neuratris, we assess whether reactive astrocytes impact molecular, cellular, functional and behavioral disease outcomes, in mouse models of Huntington's and Alzheimer's diseases (HD and AD), and more recently of demyelinating disorders. We find that reactive astrocytes have beneficial effects in HD (Escartin et al., J. Neurosci., 2006; Ben Haim et al., J. Neurosci., 2015) while they have mainly deleterious impacts in AD models (Ceyzériat et al., Acta Neuropathol. Com., 2018 ; Guillemaud et al., Neurobiol Aging, 2020).

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Virus-mediated expression of SOCS3 in astrocytes in an AD mouse model (3xTg) blunts astrocyte reaction and restores synaptic long term potentiation, a form of synaptic plasticity. 

Ceyzériat et al., Acta Neuropathol. Com., 2018. In collaboration with A. Panatier.



Grants and Awards

  • Fondation Vaincre Alzheimer. Pilot Award to Dr. L. Ben Haim. 2021-2022. Targeting astrocyte Kir4.1 to treat depressive symptoms in Alzheimer’s disease
  • Neuratris. 2021-2023. with Prof. S. Bétuing (Sorbonnes Université). BeCoMe. From Behaviour to Connectivity and Metabolism: Huntington's Disease preclinical assessment of CYP46A1 gene therapy. 
  • ANR PRC. 2020-2024.Coordinated by S. Betuing (Sorbonnes Université). Fine tuning of Sterol signalling for efficient striatal protection in Huntington's disease
  • Prix Joël Ménard  2019 in basic science on Alzheimer’s disease
  • France Alzheimer 2020-2022. Coordinated by M. Cohen-Salmon (Collège de France). Alteration of astrocyte local translation: a pathogenic mechanism in Alzheimer’s disease  
  • Fondation Maladies Rares GenOmics. 2019-2020. Collaboration with E. Bonnet (CNRGH, Evry).
  • Microglial cells: the third element for mutant Huntingtin clearance in Huntington's disease?
  • Neuratris. 2018-2021. Coordinated by F. Ortiz (Univ. Autónoma de Chile). Role of reactive astrocytes at the different stages of remyelination in an in vivo model of multiple sclerosis.
  • Association Huntington France. 2018-2019. Reactive astrocytes as anti-aggregation partners for neurons in Huntington's disease.
  • Bronze medal award from CNRS, 2017.
  • ANR Tremplin-ERC. 2017-2018. Decoding the complexity of astrocyte reactivity in neurodegenerative diseases.
  • Ligue Européenne Contre la Maladie d'Alzheimer, LECMA. 2016-2018. Targeting the JAK-STAT3 pathway in reactive astrocytes for Alzheimer's disease.
  • Fédération pour la Recherche sur le Cerveau, FRC. 2016-2018. Collaboration with A. Panatier (Neurocentre Magendie, Bordeaux). Reactive astrocytes: new therapeutic targets to correct synaptic deficits in neurodegenerative diseases?
  • ANR Young Investigator grant. 2010-2014. Selective modulation of reactive astrocytes: In vivo monitoring by magnetic resonance and contribution to neuronal death in Huntington's disease.


Team members
  • Lucile Ben Haim. Post-doc. FRM Fellowship. 2020-2023
  • Miriam Riquelme Peréz. PhD, Fellowship Amont-Aval CEA. 2019-2022
  • Maria-Angeles Carrillo-de Sauvage. Engineer CNRS. Since 2015
  • Tom Lakomy, Master1 student, 2021
Alumni
  • Océane Guillemaud. PhD student, Fellowship Amont-Aval CEA. 2017-2020
  • Laurene Abjean. PhD student, DIM Cerveau et Pensée. 2015-2019
  • Raul Pulgar Sepulveda. Exchange student from Univ. Autonoma de Chile. 2019
  • Ludmila Juricek. Post-doctoral fellow ANR. 2017-2019
  • Kelly Ceyzériat. PhD student, IRTELIS CEA. 2014-2017
  • Elena Saavedra-Lopez. Exchange PhD student from Univ. Autonoma de Barcelona. 2018
  • Lucile Ben Haim. PhD student, IRTELIS CEA. 2011-2014
  • Maria-Angeles Carrillo-de Sauvage. Post-doctoral fellow ANR. 2011-2013
  • Fabien Aubry. Technician ANR. 2012-2013
  • Ana-Clara Bobadilla. Master 1. 2009

Main collaborations

  • Drs. S. Brohard & E. Bonnet, Centre National de Recherche en Génomique Humaine (CNRGH), Evry.
  • Dr. M. Cohen-Salmon, Collège de France, Paris.
  • Dr. F. Ortiz, Universidad Autónoma de Chile, Santiago, Chili.
  • Pr. S. Bétuing, Paris Sorbonne Université, Paris.
  • Dr. H. Hirbec, Institut de Génomique Fonctionnelle, Montpellier
  • Dr. F. Gambino, Institut Interdisciplinaire de Neurosciences (IINS), Bordeaux.
  • Dr. N. Rouach, Collège de France, Paris.
  • Drs. A. Panatier & S. Oliet, Neurocentre Magendie, Bordeaux. 


Selection of publication

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington's disease
Abjean L, Ben Haim L*, Riquelme-Perez M*, Gipchtein P, Derbois C, Palomares MA, Petit F, Hérard AS, Gaillard MC, Guillermier M, Gaudin-Guérif M, Sagar N, Dufour N, Robil N, Kabani M, Melki R, De la Grange P, Bemelmans AP, Bonvento G, Deleuze JF, Hantraye P, Bonnet E, Brohard S, Olaso R, Brouillet E, Carrillo-de Sauvage MA, Escartin C.


Reactive astrocyte nomenclature, definitions, and future directions 
Escartin C*, Galea E*, […77 authors…], Sofroniew MV*, Verkhratsky A*  
Nat Neurosci. 2021. 24 : 312-25
* co-corresponding authors.

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease. 
Guillemaud O.*, Ceyzériat K.*, Saint-Georges T., Cambon K., Petit F., Ben Haim L., . . . Escartin C.  
Neurobiology of Aging. 2020. 90:135-46
* co-first authors.


Questions and (some) answers on reactive astrocytes.
Escartin C, Guillemaud O, Carrillo-de Sauvage M.
Glia. 2019. 67(12):2221-47

Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease.
Ceyzériat K, Ben Haim L, Denizot A, Pommier D, Matos M, Guillemaud O, Palomares MA, Abjean L, Petit F, Gipchtein P, Gaillard MC, Guillermier M, Bernier S, Gaudin M, Aurégan G, Joséphine C, Dechamps N, Veran J, Langlais V, Cambon K, Bémelmans A, Baijer J, Bonvento G, Dhenain M, Deleuze JF, Oliet SHR, Brouillet E, Hantraye P, Carrillo de Sauvage MA, Olaso R, Panatier A, Escartin C. 

Elusive roles for reactive astrocytes in neurodegenerative diseases. 
Ben Haim L, Carrillo-de Sauvage M-A, Ceyzériat K, Escartin C. 
Front. Cell. Neurosci. 2015. 9:278

The neuroprotective agent CNTF decreases neuronal metabolites in the rat striatum : an in vivo multimodal magnetic resonance imaging study.
Carrillo-de Sauvage M-A, Flament J, Bramoulle Y, Ben Haim L, Guillermier M, Berniard A, Auregan G, Houitte D, Brouillet E, Bonvento G, Hantraye P, Valette J, Escartin C.
J Cereb Blood Flow Metab. 2015. 35:917-21.

The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's disease.
Ben Haim L, Ceyzériat K, Carrillo-de Sauvage M-A, Aubry F, Auregan G, Guillermier M, Ruiz M, Petit F, Houitte D, Faivre E, Vandesquille M, Aron-Badin R, Dhenain M, Déglon N, Hantraye P, Brouillet E, Bonvento G, Escartin C.
J Neurosci. 2015. 35(6):2817-29.

Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.
Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C, Ezan P, Cohen-Salmon M, Benchenane K, Abudara V, Dufour A, Lübke JH, Déglon N, Knott G, Holcman D, Rouach N.
Nat Neurosci. 2014. 17(4):549-58.

Reactive astrocytes overexpress TSPO and are detected by TSPO PET imaging.
Lavisse S, Guillermier M, Hérard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dollé F, Delzescaux T, Bonvento G, Hantraye P, Escartin C.
J. Neurosci. 2012. 32(32):10809-18.