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Cell-Cell Interactions in Neurodegenerative diseases: Models and Biotherapies

​MIRCen

> CO-DIRECTION :

 Alexis BEMELMANS (CEA)


 Gilles BONVENTO (DR2 INSERM)


 Anselme PERRIER (DR2 INSERM)


Published on 26 November 2021

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Research focus and objectives of the team

Our working hypothesis is that the selective neuronal dysfunctions and death occurring in many neurodegenerative diseases originate not only from neuron-intrinsic impairments but also from the convergence of dysfunctions and damages developed within multiple cell types in specific brain areas. This includes synaptic interactions between the most vulnerable neurons within neuronal networks (e.g. striatal and cortical neurons in Huntington's disease), as well as functional interactions between these neurons and neighboring glial cells such as astrocytes or microglia. In order to interrogate the respective role of specific cell populations, we are developing innovative in cellulo (rodent primary neural cultures and human induced pluripotent stem cells (iPS)) and in vivo (rodents and non-human primates with Team 6) models of Huntington's, Parkinson's and Alzheimer's disease with viral vectors. In parallel we make use of the biological resources, tools and models created to design, develop and assess new biotherapies including in particular gene and substitutive cell therapy approaches. Overall, we aim at:

     1.Investigate the molecular basis of regional vulnerability in neurodegenerative diseases 

  • Decipher cell-intrinsic molecular pathways responsible for the vulnerability of specific neurons
  • Identify determinants of synaptic activity-dependent modulation of striatal neurons homeostasis
  • Determine spreading properties and functional consequences of misfolded and aggregated tau, α-synuclein and mutant-HTT proteins

     2. Elucidate the role of neuron-glia interactions during the course of neurodegeneration

  • How do dysfunctions in astrocytes contribute to neuronal vulnerability in HD?
  • What is the contribution of metabolic astrocyte-neuron cross-talks in AD?
  • What role does microglia play in the propagation of pathological Tau species?

     3.Design and assess innovative biotherapies for neurodegenerative diseases

  • Set-up innovative in vivo models of NDs to progress towards better diagnostics and therapies
  • Improve AAV vector delivery and biodistribution for CNS targeting
  • Develop biotherapies to target mutant genes such as Huntingtin
  • Drive hPSC therapy for Huntington's disease towards clinical application

You will find below the summary of two research projects that are ongoing in the team.

Role of glial cells in tauopathies

Tauopathies are characterized by the progressive accumulation of abnormal forms of Tau protein in the brain. Most often, Tau aggregates are found in neurons, but in some tauopathies, Tau aggregates are also detected in astrocytes. Yet both their origin and the consequences of their accumulation are unknown.

In collaboration with Université de Lille, we developed rodent models of tauopathies overexpressing tau variants with a distinct propensity to aggregate. We showed that astrocytic Tau pathology can be secondary to neuronal pathology. Using new gene transfer-based tools, we also demonstrated a transfer of Tau between neurons and astrocytes. We found severe toxicity of soluble hyperphosphorylated forms of Tau for specific populations of astrocytes. Our data suggest that astrocytes are not mere bystanders of neuronal pathology and that Tau pathology in astrocytes may significantly contribute to clinical symptoms.

    Figure 1 : Our working hypothesis is based on the bi-directional exchange of pathological Tau protein between neurons and astrocytes (left). Confocal image showing the presence of hyperphosphorylated Tau (AT100, red) in neurons and in one astrocyte (GFAP green, white arrow) in 18-month old Thy-Tau22- mouse (right).


    Figure 1 : Notre hypothèse de travail est basée sur l'échange bidirectionnel de protéine Tau pathologique entre les neurones et les astrocytes (à gauche). Image confocale montrant la présence de Tau hyperphosphorylée (AT100 en rouge) dans les neurones et dans un astrocyte (GFAP en vert, flèche blanche) chez la souris Thy-Tau22 de 18 mois (à droite).


Along with astrocytes, microglial cells are involved in the neuroinflammatory response to Tauopathy. The variants of TREM2, a cell surface receptor expressed by microglia, confer a risk of developing AD comparable to the ε4 allele of the APOE gene. This suggests that in addition to responding to the pathological process, these glial cells may actually play a key role in the emergence of the disease. We investigated the impact of TREM2 deficiency on the severity of Tauopathy in the THY-Tau22 transgenic line, a well-characterized model of tauopathy. We found an increase in the severity of tauopathy in TREM2-deficient mice. This exacerbation of the pathology was associated with a reduction in microglial activation indicated by typical morphological features and altered expression of specific markers. Our study confirms that a defect in microglial TREM2 signaling leads to an increase in neuronal tauopathy. 


Figure 2 : AT100 staining showing the increase accumulation of tauopathy in the CA1 layer of the hippocampus in 12-month-old Tau22 mice deficient for Trem2 (Vautheny et al., Neurobiology of Disease 2021)


Impact of HTT lowering at the synapse and in human astrocyte 

Lowering or inactivating altogether of mutant Huntingtin (mut-HTT) are likely the two most undisputed and direct paths to reduce HD symptoms and may be in the future to cure HD patients. Beyond the issues related to delivery and cost of such therapies, the question of the consequences of concomitant lowering or complete inactivation of wild type (wt) HTT isoforms has not yet been properly addressed. Indeed, evidence show that wt-HTT has crucial role in brain cell functions. Lowering/inactivating wt HTT allele may be detrimental. We are working on this topic using an “in cellulo” model of the cortico-striatal tripartite synapse reconstructed with human pluripotent stem cells (hPSCs). We believe that hPSC-based cellular models of neuron-neuron and neuron-astrocyte interactions at the synapse provide remarkable perspectives for the study of HTT protein. We focus in particular our work on the study of astrocytic wt-HTT and mut-HTT functions and their modulations by HTT-lowering/editing treatments at the synapse.


Figure 3 : Co-culture of cortical neurons and astrocyte derived from wt-human iPSC: Immunstaining of neuronal (MAP2 red) and glial (GFAP green) markers day in vitro 57.



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Team members



principal investigators in the team



engineers/technicians

  • Gwennaëlle AUREGAN (CEA Tech.)
  • Noëlle  DUFOUR  (CEA Eng. )
  • Donya  EL AKROUTI  (CEA Eng.)
  • Marie-Claude GAILLARD   (CEA Eng.)
  • Charlène JOSEPHINE  (CEA Tech.)
  • Julien MITJA  (CEA Tech.)

 

POST-DOCS / PhD students


  • Emma  AUGUSTIN (PhD Student)
  • Laurent COTTER  (Postdoc)
  • Pauline LEAL (PhD student)
  • Mathilde LOUCA  (PhD Student)
  • Emmanuel THAN-TRONG (Postdoc) 


external collaborators

  • Frederic Saudou (GIN Grenoble)
  • Nicole Deglon (CHUV Lausanne, Switzerland)
  • Jean-Michel Peyrin (IBPS, Paris)
  • Anne Rosser (Cardiff Univ, UK)
  • Nathalie Rouach (Collège de France, Paris)
  • Juan Bolanos (Univ. Salamanca, Spain)
  • Giovanni Marsicano ; Aude Panatier ; Stéphane Oliet (Neurocentre Magendie, Bordeaux, France)
  • Huu Phuc Nguyen  (Hoa : Bochum, Germany)
  • Jing Wang / Jean-Luc Puel (Institut des Neurosciences de Montpellier)
  • Cendra Agulhon (Centre de recherche des Cordeliers)
  • Juliette Van Steenwinckel / Pierre Gressens (NeuroDiderot, Paris)
  • David Blum / Luc Buée (Univ. Lille, Inserm, CHU Lille, U1172 )
  • Nathalie Le Floch Leleu (UVSQ)
  • Nathalie Bonnefoy (CNRS I2BC, Gif sur Yvette)
  • Marie-Pierre Golinelli (ICSN, Gif sur Yvette)
  • Laurette Boutillier (LNC, Strasbourg)
  • Serge Charpak (IDV Paris)

 Recent fundings

  • Neuratris – Innovation for translational neuroscience: Contribution of glial cells to synaptic phagocytosis in Tauopathies (2021-22)

  • Neuratris – Innovation for translational neuroscience: Satellite glial cell-proprioceptor interactions: implications for spinal muscular atrophy, amyotrophic lateral sclerosis and Friedreich's ataxia (2020-22)

  • CEA – Bottom/up program: VisioGlia - Targeting P2RY12 purinergic receptors for in vivo microglial imaging (2019-21)
  • 2013-2015 : Association France-Alzheimer – Fondation de France - Bruno Cauli (CNRS UMR 7102, UMPC) ; Stéphane Oliet (INSERM U862, Bordeaux) Rôle des astrocytes dans la maladie d'Alzheimer (coordinateur du projet)
  • 2016-2018 : Fondation Plan Alzheimer Role of astrocytic 3-phosphoglycerate dehydrogenase in AD (coordinateur du projet)
  • 2018-2023 : ANR Adorastrau - David Blum, Laurette Boutillier Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer (partenaire du projet)
  • 2020-2022: Fondation pour la Recherche Médicale - Fondation Alzheimer - Serge Charpak, IDV Imaging glycolytic and vascular dysfunction in early Alzheimer Disease (coordinateur du projet)


Selected Publications

Astrocyte-neuron metabolic cooperation shapes brain activity. Bonvento G, Bolaños JP. Cell Metab. 2021 Aug 3;33(8):1546-1564. doi:10.1016/j.cmet.2021.07.006

Neuronal Tau species transfer to astrocytes and induce their loss according to Tau aggregation state. Maté de Gérando Anastasie, d'Orange Marie, Augustin Emma, Joséphine Charlène, Aurégan Gwénaelle, Gaudin-Guérif Mylène, Guillermier Martine, Hérard Anne- Sophie, Stimmer Lev, Petit  Fanny, Gipchtein Pauline, Jan Caroline, Escartin Carole, Selingue Erwan, Carvalho Kévin, Blum David, Brouillet Emmanuel, Hantraye Philippe, Gaillard Marie-Claude, Bonvento Gilles, Bemelmans Alexis-Pierre, Cambon Karine. BRAIN, April 2021, https://doi.org/10.1093/brain/awab011

The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo. Cresto N, Gardier C, Gaillard MC, Gubinelli F, Roost P, Molina D, Josephine C, Dufour N, Auregan G, Guillermier M, Bernier S, Jan C, Gipchtein P, Hantraye P, Chartier-Harlin MC, Bonvento G, Van Camp N, Taymans JM, Cambon K, Liot G, Bemelmans AP, Brouillet E. Int J Mol Sci. 2021 Jun 22(13):6760. doi: 10.3390/ijms22136760.

THY-Tau22 mouse model accumulates more tauopathy at late stage of the disease in response to microglia deactivation through TREM2 deficiency. Vautheny A, Duwat C, Aurégan G, Joséphine C, Hérard AS, Jan C, Mitja J, Gipchtein P, Gaillard MC, Buée L, Blum D, Hantraye P, Bonvento G, Brouillet E, Cambon K, Bemelmans AP. Neurobiology of Disease 2021 Jul;155:105398. doi: 10.1016/j.nbd.2021.105398. Epub 2021 May 18.

Impairment of glycolysis-derived L-serine production in astrocytes contributes to cognitive deficits in Alzheimer's disease Le Douce J, Maugard M, Veran J, Matos M, Jégo P, Vigneron P-A, Faivre E, Toussay X, Vandenberghe M, Balbastre Y, Piquet J, Guiot E, Nguyet Thuy Tran, Taverna M, Marinesco S, Koyanagi A, Furuya S, Gaudin-Guérif M, Goutal S, Ghettas A, Pruvost A, Bemelmans AP, Gaillard M-C, Cambon K, Stimmer L, Sazdovitch V, Duyckaerts C, Knott G, Hérard A-S, Delzescaux T, Hantraye P, Brouillet E, Cauli B,. Oliet S, Panatier A, Bonvento G. Cell Metabolism, 2020 Mar 3;31(3):503-517.e8. doi: 10.1016/j.cmet.2020.02.004.

MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates. Romina Aron Badin, Aurore Bugi , Susannah Williams , Marta Vadori , Marie Michael , Caroline Jan, Alberto Nassi, Sophie Lecourtois, Antoine Blancher , Emanuele Cozzi , Philippe Hantraye , Anselme L Perrier   Nat Commun 2019 Sep 25;10(1):4357. doi: 10.1038/s41467-019-12324-0.

Propagation of α-Synuclein Strains within Human Reconstructed Neuronal Network. Gribaudo S, Tixador P, Bousset L, Fenyi A, Lino P, Melki R, Peyrin JM, Perrier AL. Stem Cell Reports. 2019 Feb 12;12(2):230-244. doi: 10.1016/j.stemcr.2018.12.007. Epub 2019 Jan 10.

The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo. Cresto N, Gaillard MC, Gardier C, Gubinelli F, Diguet E, Bellet D, Legroux L, Mitja J, Auregan G, Guillermier M, Josephine C, Jan C, Dufour N, Joliot A, Hantraye P, Bonvento G, Déglon N, Bemelmans AP, Cambon K, Liot G, Brouillet E. Neurobiology of  Disease 2019 Oct 9:104614. doi: 10.1016/j.nbd.2019.104614.

 Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat. d'Orange M, Aurégan G, Cheramy D, Gaudin-Guérif M, Lieger S, Guillermier M, Stimmer L, Joséphine C, Hérard AS, Gaillard MC, Petit F, Kiessling MC, Schmitz C, Colin M, Buée L, Panayi F, Diguet E, Brouillet E, Hantraye P, Bemelmans AP, Cambon K. BRAIN 2018 Feb 1;141(2):535-549. doi: 10.1093/brain/awx342.

 The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. Galvan L, Francelle L, Gaillard MC, de Longprez L, Carrillo-de Sauvage MA, Liot G, Cambon K, Stimmer L, Luccantoni S, Flament J, Valette J, de Chaldée M, Auregan G, Guillermier M, Joséphine C, Petit F, Jan C, Jarrige M, Dufour N, Elalouf JM , Bonvento G, Humbert S, Saudou F, Hantraye P, Merienne K, Bemelmans AP, Perrier A, Déglon N, Brouillet E. BRAIN May 1;141(5):1434-1454. doi: 10.1093/brain/awy057.

 Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing. Cambon K, Zimmer V, Martineau S, Gaillard MC, Jarrige M, Bugi A, Miniarikova J, Rey M, Hassig R, Dufour N, Auregan G, Hantraye P, Perrier AL, Déglon N. Mol Ther Methods Clin Dev. 2017 May 11;5:259-276. doi: 10.1016/j.omtm.2017.05.001.

mRNA trans-splicing in gene therapy for genetic diseases. Berger A, Maire S, Gaillard MC, Sahel JA, Hantraye P, Bemelmans AP. Wiley Interdisciplinary Reviews RNA 2016 Jul;7(4):487-98. doi: 10.1002/wrna.1347. Epub 2016 Mar 28.

Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa. Berger A, Lorain S, Joséphine C, Desrosiers M, Peccate C, Voit T, Garcia L, Sahel JA, Bemelmans AP. Molecular Therapy 2015 May;23(5):918-930. doi: 10.1038/mt.2015.11. Epub 2015 Jan 26.

Previous members

Technician

  • Mylene Gaudin

Post-docs

  • Morgane Louessard
  • Laura Garcia-Gonzalez
  • Pierrick Jégo
  • Emilie Hangen
  • Anne Rocher
  • Emilie Faivre

Students/PhD Students

  • Anastasie Maté de Gérando
  • Marie d'Orange 
  • Charlotte Duwat
  • Audrey Vautheny
  • Séverine Maire
  • Pierre-Antoine Vigneron
  • Marianne Maugard
  • Juliette Le Douce
  • Mathilde Faideau
  • Noémie Cresto
  • Camille Gardier
  • Francesco Gubinelli
  • Laurie Galvan
  • Laetitia Francelle
  • Lucie de Longprez
  • Fanny Lebourg