Portal de investigação
Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Socodato, R
- Portuga, CC
- Canedo, T
- Almeida, TO
- Henriques, JF
- Vaz, SH
- Magalhaes, J
- Baptista, FI
- Alves, RL
- Coelho Santos, V
- Silva, AP
- Paes de Carvalho, R
- Magalhaes, A
- Brakebusch, C
- Sebastiao, AM
- Summavielle, T
- Ambrosio, AF
Unidades de investigação
Abstract
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.
Dados da publicação
- ISSN/ISSNe:
- 2211-1247, 2211-1247
- Tipo:
- Article
- Páginas:
- -
- Link para outro recurso:
- www.scopus.com
Cell Reports Cell Press
Citações Recebidas na Web of Science: 49
Citações Recebidas na Scopus: 53
Documentos
- Não há documentos
Filiações
Keywords
- SMALL GTPASE RHOA; GLUTAMATE RELEASE; OBJECT RECOGNITION; CELL-LINES; KINASE; MACROPHAGES; ACTIVATION; FATE; MICE; NEUROTOXICITY
Campos de estudo
Financiamento
Proyectos asociados
Emergence of multidrug cross-resistance between agricultural and human antifungals in clinically relevant species of Aspergillus and Candida
Investigador Principal: Acácio Agostinho Gonçalves Rodrigues
Estudo Clínico Académico . 2019
Citar a publicação
Socodato R,Portuga CC,Canedo T,Rodrigues A,Almeida TO,Henriques JF,Vaz SH,Magalhaes J,Silva CM,Baptista FI,Alves RL,Coelho V,Silva AP,Paes de Carvalho R,Magalhaes A,Brakebusch C,Sebastiao AM,Summavielle T,Ambrosio AF,Relvas J. Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration. Cell Rep. 2020. 31. (12):107796. IF:9,423. (1).
