Microglial priming induced by loss of Mef2C contributes to postoperative cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a central nervous system (CNS) complication that adversely affects attention, memory and cognitive flexibility. POCD is associated with high medical costs burden and even contributes to an increased risk of death (Monk et al., 2008; Steinmetz et al., 2009; Evered and Silbert, 2018). Aging is a well-recognized risk factor for POCD (Bedford, 1955; Garrone et al., 2021) and is associated with a sensitized neuroimmune state that leads to an exaggerated inflammatory response upon immune challenge (Fonken et al., 2018); this may account for the increased incidence of POCD in elderly individuals. However, the specific mechanisms underlying the tendency of elderly individuals to be in a proinflammatory state are still unclear.

Microglia are highly specialized resident immune cells in the central nervous system (CNS) that maintain an adaptive balance between pro- and anti-inflammatory mechanisms (Prinz et al., 2019). Aging induces microglia to adopt a primed phenotype associated with a sensitized neuroimmune state in elderly individuals (Mecca et al., 2018) and in those with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease (Perry and Holmes, 2014). An exaggerated proinflammatory response upon stimulation with lipopolysaccharide (LPS) has been observed in aged microglia compared with young microglia (Frank et al., 2010). Primed microglia are not activated at baseline but are highly responsive to secondary stimuli, inducing excessive and prolonged neuroinflammation following immune challenge. This hyperresponsiveness may explain why many elderly patients suffer from POCD despite showing healthy cognition before surgery. However, the mechanisms of microglial priming in aged individuals are unclear.

Microglial priming is regulated by a variety of molecular mechanisms, termed immune checkpoints (Deczkowska et al., 2018), that prevent uncontrolled responses of adaptive immune cells (Topalian et al., 2016; Yamamoto et al., 2020). Recently, microglial priming was found to be modulated by immune checkpoints including myocyte enhancer factor 2C (Mef2C) (Deczkowska et al., 2017), CX3CL1/CX3CR1, CD200/CD200R (Biber et al., 2007; Matcovitch-Natan et al., 2016), and transforming growth factor-β (TGF-β) (Butovsky et al., 2014). Mef2C is a transcription factor of the Mef2 family that participates in the early development of a variety of human cells (Dong et al., 2017). Notably, Mef2 family members are critical mediators of cognitive health that enhance cognitive function at baseline and endow organisms with cognitive resilience, enabling them to acclimate to various forms of brain pathology (Barker et al., 2021), such as surgery-derived neuroinflammation. It is well known that cognitive resilience is reduced in elderly patients, which limits the ability of these patients to adapt to the postoperative brain pathological environment and thus leads to POCD. Previous work on Mef2C has focused on its regulation of neuronal differentiation and synaptic plasticity (Harrington et al., 2020; Cosgrove et al., 2021), but recent studies have extended the role of Mef2C to the regulation microglial function, suggesting that Mef2C restrains the microglial inflammatory response (Deczkowska et al., 2017). The aim of this study was to explore the role of Mef2C in the susceptibility of elderly patients to POCD by limiting microglial priming. We found here that a low level of Mef2C induced a microglial priming phenotype in young mice, resulting in increased neuroinflammation in the hippocampus, which could impair cognition, upon surgery, while upregulation of Mef2C in the aged mice had a salutary effect. Therefore, the microglial immune checkpoint Mef2C may be a crucial mediator that enhances cognitive resilience in aged individuals, protecting them from POCD.

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