Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration

• DOI: 10.1016/j.celrep.2020.107796
• Publication Date: 2020-06-23T14:36:31Z
• Authors: Renato Socodato; Camila C. Portugal; Teresa Canedo; Artur Rodrigues; Tiago O. Almeida; Joana F. Henriques; Sandra H. Vaz; João Magalhães; Cátia M. Silva; Filipa I. Baptista; Renata L. Alves; Vanessa Coelho-Sa...; Ana Paula Silva; Roberto Paes-de-C...; Ana Magalhães; Cord Brakebusch; Ana M. Sebastião; Teresa Summavielle; António F. Ambrósio; João B. Relvas
• Keywords: Aging; 572; Cell Survival; Nerve Degeneration / pathology; Cell Line; memory; CSK Tyrosine-Protein Kinase; Memory; rhoA GTP-Binding Protein / metabolism; Animals; RhoGTPase; Aging / metabolism; Tyrosine kinase; Neurons; Microglia / pathology; src-Family Kinases / antagonists & inhibitors; Amyloid beta-Peptides; Amyloid beta-Peptides / metabolism; Neurons / metabolism; tyrosine kinase; src-Family Kinases / metabolism; Cell Polarity; Synapses / metabolism; rhoA GTP-Binding Protein / deficiency; 3. Good health; Mice, Inbred C57BL; Phenotype; src-Family Kinases; Microglia / metabolism; Nerve Degeneration; Synapses; Microglia; Alzheimer disease; LTP; rhoA GTP-Binding Protein; Aging / pathology

AbstractNervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of ß-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimer’s disease and that low doses of Aß oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.