Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease
acta neuropathol commun. 2018-10-16; 6(1):
DOI: 10.1186/s40478-018-0606-1
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1. Acta Neuropathol Commun. 2018 Oct 16;6(1):104. doi: 10.1186/s40478-018-0606-1.
Modulation of astrocyte reactivity improves functional deficits in mouse models
of Alzheimer’s disease.
Ceyzériat K(1)(2), Ben Haim L(1)(2)(3), Denizot A(4)(5), Pommier D(4)(5), Matos
M(4)(5), Guillemaud O(1)(2), Palomares MA(6), Abjean L(1)(2), Petit F(1)(2),
Gipchtein P(1)(2), Gaillard MC(1)(2), Guillermier M(1)(2), Bernier S(1)(2),
Gaudin M(1)(2), Aurégan G(1)(2), Joséphine C(1)(2), Déchamps N(7)(8), Veran
J(4)(5), Langlais V(4)(5), Cambon K(1)(2), Bemelmans AP(1)(2), Baijer J(7)(8),
Bonvento G(1)(2), Dhenain M(1)(2), Deleuze JF(6), Oliet SHR(4)(5), Brouillet
E(1)(2), Hantraye P(1)(2), Carrillo-de Sauvage MA(1)(2), Olaso R(6), Panatier
A(4)(5), Escartin C(9)(10).
Author information:
(1)Commissariat à l’Energie Atomique et aux Energies Alternatives, Département de
la Recherche Fondamentale, Institut de Biologie François Jacob, MIRCen, 92260,
Fontenay-aux-Roses, France.
(2)Centre National de la Recherche Scientifique, Université Paris-Sud, UMR 9199,
Neurodegenerative Diseases Laboratory, 92260, Fontenay-aux-Roses, France.
(3)Present address: F.M. Kirby Neurobiology Center, Boston Children’s Hospital,
and Department of Neurology, Harvard Medical School, Boston, USA.
(4)Neurocentre Magendie, INSERM U1215, 33077, Bordeaux, France.
(5)Université de Bordeaux, 33077, Bordeaux, France.
(6)Commissariat à l’Energie Atomique et aux Energies Alternatives, Département de
la Recherche Fondamentale, Institut de Biologie François Jacob, Centre National
de Recherche en Génomique Humaine (CNRGH), F-91057, Evry, France.
(7)Commissariat à l’Energie Atomique et aux Energies Alternatives, Département de
la Recherche Fondamentale, Institut de Biologie François Jacob, Institut de
Radiobiologie Cellulaire et Moléculaire, UMR 967 92260, Fontenay-aux-Roses,
France.
(8)CEA-INSERM, Université Paris-Diderot et Université Paris-Sud, Paris, France.
(9)Commissariat à l’Energie Atomique et aux Energies Alternatives, Département de
la Recherche Fondamentale, Institut de Biologie François Jacob, MIRCen, 92260,
Fontenay-aux-Roses, France. .
(10)Centre National de la Recherche Scientifique, Université Paris-Sud, UMR 9199,
Neurodegenerative Diseases Laboratory, 92260, Fontenay-aux-Roses, France.
.
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.
DOI: 10.1186/s40478-018-0606-1
PMCID: PMC6190663
PMID: 30322407 [Indexed for MEDLINE]