The activation of inflammatory responses in the brain is potentiated by over-expressing acetylcholinesterase in myeloid lineage of transgenic mice.

Abstract

Acetylcholinesterase (AChE) has functions in neuroinflammation, beyond its classical role in neurotransmission. Understanding the role of AChE in neuroinflammation is of great significance, as it highlights the potential therapeutic targets for the treatment of neurodegenerative diseases. In an in vitro study, the expression of AChE was up-regulated in lipopolysaccharide (LPS)-induced microglia/macrophage and contrarily potentiated the inflammatory responses via disturbing the cholinergic anti-inflammatory pathway (CAP). However, the regulation of AChE in neuroinflammation has not been revealed in vivo yet. Here, we aim to uncover the inflammatory roles of microglial AChE in LPS-induced neuroinflammation by using the conditional AChE over-expression mouse model. AChE was specifically over-expressed in the myeloid cell linkage of mouse by applying CRISPR/cas9 combined with Cre-LoxP system. LPS was intraperitoneally injected into the mice to induce inflammation. The results showed that the inflammation, induced by LPS, was aggravated in the brain of transgenic mice having over-expression of AChE in microglia. The expressions of pro-inflammatory cytokines were robustly up-regulated in the brains of LPS-treated transgenic mice, as compared to the LPS-treated wildtypes. In parallel, the activations of microglia and astrocytes in hippocampus were enhanced significantly in AChE transgenic mice. Transcriptomics analysis further confirmed the severer inflammation in the transgenic mice than the wildtype after LPS administration. These findings shed light on the regulation of microglial AChE in neuroinflammation in vivo for the first time, presenting another angle to understand the role of AChE in neurodegenerative diseases.