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

• DOI: 10.1016/j.neurobiolaging.2020.02.010
• Publication Date: 2020-02-19T00:38:18Z
• Authors: Océane Guillemaud; Kelly Ceyzériat; Thomas Saint-Georges; Karine Cambon; Fanny Petit; Lucile Ben Haim; Maria-Angeles Car...; Martine Guillermier; Sueva Bernier; Anne-Sophie Hérard; Charlène Joséphine; Alexis Pierre Bém...; Emmanuel Brouillet; Philippe Hantraye; Gilles Bonvento; Carole Escartin
• Keywords: MESH: Signal Transduction; STAT3 Transcription Factor; 0301 basic medicine; MESH: Hippocampus; MESH: Mice, Transgenic; JAK-STAT3 pathway; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Amyloidogenic Proteins; Mice, Transgenic; tau Proteins; Hippocampus; MESH: Janus Kinase 2; 03 medical and health sciences; Neuroinflammation; Alzheimer Disease; Animals; MESH: Animals; SOCS3; Phosphorylation; MESH: Amyloidogenic Proteins; MESH: Phosphorylation; Neuroinflammation.; MESH: STAT3 Transcription Factor; Janus Kinase 2; MESH: tau Proteins; 3. Good health; MESH: Astrocytes; Disease Models, Animal; Astrocytes; Reactive astrocytes; Alzheimer disease; Tau; MESH: Disease Models, Animal; MESH: Alzheimer Disease; Signal Transduction

ABSTRACTIn 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.