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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Socodato, R (Author) Other; Portuga, CC (Author) Other; Canedo, T (Author) Other; Rodrigues, A (Author) Other; Almeida, TO (Author) Other; Henriques, JF (Author) Other; Vaz, SH (Author) Other; Magalhaes, J (Author) Other; Silva, CM (Author) Other; Baptista, FI (Author) Other; Alves, RL (Author) Other; Coelho Santos, V (Author) Other; Silva, AP (Author) Other; Paes de Carvalho, R (Author) Other; Magalhaes, A (Author) Other; Brakebusch, C (Author) Other; Sebastiao, AM (Author) Other; Summavielle, T (Author) Other; Ambrosio, AF (Author) Other; Relvas, JB (Author) FMUP

Journal

Title: Cell Reports

Vol. 31

ISSN: 2211-1247

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 11 Citations

Other information

Authenticus ID: P-00S-C67

DOI: 10.1016/j.celrep.2020.107796

Abstract (EN): Nervous tissue homeostasis requires the 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 long-term potentiation [LTP], formation of beta-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of A beta oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 28