Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice

Abstract

Microglia are the primary source of transglutaminase 2 (TGM2) in the brain; however, the roles of microglial TGM2 in neural development and disease are still not well known. The aim of this study is to elucidate the role and mechanisms of microglial TGM2 in the brain. A mouse line with a specific knockout of Tgm2 in microglia was generated. Immunohistochemistry, Western blot and qRT‐PCR assays were performed to evaluate the expression levels of TGM2, PSD‐95 and CD68. Confocal imaging, immunofluorescence staining and behavioural analyses were conducted to identify phenotypes of microglial TGM2 deficiency. Finally, RNA sequencing, qRT‐PCR and co‐culture of neurons and microglia were used to explore the potential mechanisms. Deletion of microglial Tgm2 causes impaired synaptic pruning, reduced anxiety and increased cognitive deficits in mice. At the molecular level, the phagocytic genes, such as Cq1a, C1qb and Tim4, are significantly down‐regulated in TGM2‐deficient microglia. This study elucidates a novel role of microglial TGM2 in regulating synaptic remodelling and cognitive function, indicating that microglia Tgm2 is essential for proper neural development.

Exploration of the shared genetic biomarkers in Alzheimer’s disease and chronic kidney disease using integrated bioinformatics analysis

“…[ 47 ] Studies show that deletion of TGM2 in microglia leads to impaired synaptic pruning and cognitive impairment and exacerbates pathological damage in AD in mice. [ 48 ] In the single-cell analysis conducted in this study, it was observed that AFF1 exhibited significant expression in microglia, indicating its potential role in enhancing synaptic remodeling and cognitive function through the upregulation of TGM2 levels, specifically in microglia. Furthermore, the single-cell analysis also revealed significant expression of AFF1 in immune cells and fibroblasts, primarily observed in individuals with CKD.…”

Origin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell

“…In the postnatal developing brain, the absence of microglial EED, a Polycomb protein vital for synaptic pruning, led to the upregulation of phagocytosis-related genes [ 92 ]. Contrariwise, the deletion of microglial Tgm2 in mice resulted in the downregulation of microglial phagocytic-related genes accompanied by synaptic pruning and cognitive impairment [ 93 ]. A P2RX7-induced proliferation of embryonic spinal cord microglia was proposed after comparison of wild-type and P2rx7 -/- embryos.…”