TREM2-regulated microglial reactivity confers resilience against vascular contributions to white matter injury and cognitive decline

Abstract

Cerebrovascular disease is a major contributor to subcortical white matter pathology, vascular cognitive impairment (VCI) and dementia. Although the precise pathophysiological mechanisms remain unclear, it is increasingly evident that microglial responses may be critical to the development and progression of cerebrovascular disease and its cognitive consequences. To investigate this further, we assessed microglial reactivity in white matter regions of human post- mortem tissue with pathologically confirmed cerebrovascular injury. In parallel, we implemented a mouse model of VCI induced by bilateral carotid artery stenosis (BCAS) and determined the impact of genetically deleting the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial homeostatic and reactive functions. Using immunohistochemistry (IHC) and quantitative polymerase chain reaction (QPCR) we observed increased microglial reactivity and TREM2 expression in our human cohort implicating TREM2 signalling in microglial responses to cerebrovascular. In mice, IHC and flow cytometric analysis revealed Trem2 deficiency blunted microglial reactivity following BCAS (1 month). Transcriptomic analysis of Trem2-/- microglia also demonstrated attenuated induction of gene expression modules associated with inflammation, lysosomal function, lipid processing and metabolic reprogramming following BCAS (data not shown). Importantly, this was associated with greater white matter injury compared to wildtype (WT) counterparts in the absence of overt cognitive changes. Following longer durations of BCAS (6 months), Trem2-/- mice exhibited additional parenchymal and vascular pathologies associated with impairments in spatial learning and memory whilst such changes were largely absent in WT mice. Interestingly, assessment of microglia by IHC demonstrated reduced interaction with white matter cerebrovasculature in Trem2-/- mice. Taken together, these data support a role for microglia in cerebrovascular contributions to cognitive decline and dementia. Therefore, targeting regulators of microglia reactivity may provide means to influence cerebrovascular disease trajectory and associated cognitive changes. While further work is required to delineate the precise function of microglia in this context, our preclinical data suggest TREM2-regulated microglial responses to cerebrovascular insult are important for maintenance of brain health and cognitive resilience. Future work will continue to decipher how TREM2 mediates such resilience with particular focus on interaction with other cell types within the neurogliovascular unit.