| Popis: |
Microglia, the resident immune cells of the central nervous system, maintain brain homeostasis and respond to injury and disease. In Alzheimer’s disease (AD), microglia play complex roles, having both positive and negative effects on disease progression. For instance, microglial phagocytosis of toxic amyloid peptides may be beneficial while their excessive release of inflammatory mediators can exacerbate the pathology. Modulating microglial activity to promote the uptake of amyloid peptides while limiting their inflammatory response could provide an effective therapeutic approach to treating AD. Different G protein-coupled receptors (GPCRs) have been shown to modulate microglial activity such as phagocytosis and the release of cytokines in vitro, however their roles in vivo are not entirely understood. To study the role of microglial GPCRs in vivo, we generated mice expressing either hM3Dq or hM4Di Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively in microglia. We aimed to explore whether chemogenetics can be employed to manipulate microglial activity in vivo and whether this approach can be used to modulate neuroinflammation and Ab-clearance in a mouse model of AD. Interestingly, activation of hM3Dq increased the phagocytic activity of primary microglia and promoted their uptake of amyloid oligomers. Furthermore, acute activation of hM3Dq increased the expression of pro-inflammatory cytokines in the brain while repeated clozapine N-oxide (CNO) treatment had an anti-inflammatory effect. Remarkably, repeated hM3Dq activation prior to lipopolysaccharide-induced neuroinflammation attenuated pro-inflammatory cytokine expression and the associated behavioural deficits. In contrast, activation of hM4Di did not modulate the phagocytic activity of microglial nor neuroinflammation in mice. In applying this chemogenetic approach to the AppNL-G-F AD mouse model, chronic activation of hM3Dq or hM4Di did not affect cortical amyloid-beta levels nor plaque deposition. Furthermore, chronic CNO treatment had little effect on the expression of pro-inflammatory cytokines in the cortex of hM3Dq- and hM4Di-AppNL-G-F mice. Interestingly, the subset of microglia expressing hM3Dq or hM4Di were associated closely with amyloid plaques and displayed altered morphology, suggesting that plaques may influence the phenotypes of microglia. Overall, we used chemogenetics to further the understanding of microglial function in vivo under homeostatic and disease conditions. |
