Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease

• DOI: 10.1186/s40478-018-0606-1
• Publication Date: 2018-10-15T18:39:18Z
• Authors: Kelly Ceyzériat; Lucile Ben Haim; Audrey Denizot; Dylan Pommier; Marco Matos; Océane Guillemaud; Marie-Ange Palomares; Laurene Abjean; Fanny Petit; Pauline Gipchtein; Marie-Claude Gail...; Martine Guillermier; Sueva Bernier; Mylène Gaudin; Gwenaëlle Aurégan; Charlène Joséphine; Nathalie Déchamps; Julien Veran; Valentin Langlais; Karine Cambon; Alexis P Bemelmans; Jan Baijer; Gilles Bonvento; Marc Dhenain; Jean-François Del...; Stéphane H R Oliet; Emmanuel Brouillet; Philippe Hantraye; Maria-Angeles Car...; Robert Olaso; Aude Panatier; Carole Escartin
• Keywords: Viral vectors; Male; JAK2-STAT3 pathway; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Mice, Transgenic; Mouse models; Hippocampus; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Apolipoproteins E; Neuroinflammation; Alzheimer Disease; Glial Fibrillary Acidic Protein; Presenilin-1; Animals; Aspartic Acid Endopeptidases; RC346-429; Extracellular Signal-Regulated MAP Kinases; Maze Learning; JAK2-STAT3 pathway; 0303 health sciences; Amyloid beta-Peptides; Research; Signaling cascades; Excitatory Postsynaptic Potentials; Janus Kinase 2; Disease Models, Animal; Astrocytes; Mutation; Reactive astrocytes; Neurology. Diseases of the nervous system; Amyloid Precursor Protein Secretases; Alzheimer’s disease

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer's disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer's disease.