Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration

Abstract

Nervous 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.

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

“…Similarly, Mapk/ Erk-signaling is induced by Plcγ2 activation [4] and regulates pathways related to survival, proliferation, differentiation, and inflammatory responses in brain immune cells and other cell types [22]. Rac1 and RhoA can be activated via Trem2/Plcγ2-signaling [23][24][25] and play pivotal roles in microglia activation, migration, phagocytosis, and neuronal protection [25][26][27][28][29]. Thus, the higher expression of such targets could be directly associated with Plcγ2-dependent Ip3 signaling and is in line with improved survival, inflammatory response, and phagocytosis observed in KI macrophages.…”

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus

“…In addition to the direct stimulation of necroptosis by TNF, this pro-inflammatory cytokine may play a role in neurodegeneration by stimulating ROS generation in neurons and glia [11,40,46] and promoting glutamate release by microglia [14,51]. In addition to the reduction in cell death and pMLKL expression, pre-treatment with RIPK1, RIPK3 and MLKL small molecule inhibitors also resulted in reduced beading of neurites, indicative of reduced neurodegeneration, and reduced intracellular ROS caused by TNF signaling.…”

RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury

“…Different strategies might overcome this issue. Manipulation of RhoA should be as specific to neurons as possible to avoid a negative influence on other cell types (Socodato et al, 2020). This could be achieved by neuron-specific targeting of the RhoA gene itself or through gene therapy approaches using the appropriate combination of capsid serotype and target gene promotor (Blessing and Dé glon, 2016;Shevtsova et al, 2005).…”