News

home News

[20724 저널발표] Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration

김행준 │ 2020-07-23

HIT

122

Cell Reports
Volume 31, Issue 12, 23 June 2020, 107796
Journal home page for Cell Reports

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

Under a Creative Commons license
open access

Highlights

Microglia lacking Rhoa become neurotoxic

Rhoa ablation in microglia leads to amyloidosis, synapse loss, and memory deficits

Rhoa ablation in microglia is sufficient to produce an AD-like pathology

Rhoa activation is decreased in microglia from AD mice

Summary

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 β-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 Aβ 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.


https://www.sciencedirect.com/science/article/pii/S2211124720307774?via%3Dihub#app2





Prev [200716 저널발표] Microglial remodeling of the ECM promotes synapse plasticity
Next [20724 저널발표] Physiological blood–brain transport is impaired with age ...