Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

Océane Guillemaud (1, 2) , Kelly Ceyzériat (1, 2) , Thomas Saint-Georges (1, 2) , Karine Cambon (1, 2) , Fanny Petit (1, 2) , Lucile Ben Haim (1, 2) , Maria-Angeles Carrillo-de Sauvage (1, 2) , Martine Guillermier (1, 2) , Sueva Bernier (1, 2) , Anne-Sophie Herard (1, 2) , Charlène Joséphine (1, 2) , Alexis-Pierre Bemelmans (1, 2) , Emmanuel Brouillet (1, 2) , Philippe Hantraye (1, 2) , Gilles Bonvento (1, 2) , Carole Escartin (1, 2)

1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
2 MIRCEN - Service MIRCEN

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2- STAT3 pathway, a central cascade controlling astrocyte reaction. We aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

Keywords: Reactive astrocytes; Alzheimer disease; Tau; JAK-STAT3 pathway; SOCS3; Neuroinflammation.

Domains: Neurobiology

Océane Guillemaud, Kelly Ceyzériat, Thomas Saint-Georges, Karine Cambon, Fanny Petit, et al.. Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease. 2019. ⟨cea-02392438⟩