CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia. Overall design: Adult C57BL/6J females were subjected to Sham or MI surgery (n=5 per group). 7 days after surgery, brains were collected and processed into single cell solutions using a Neuronal Tissue Dissociation Kit (P) following manufacturer's instructions. Myelin debris was removed by density gradient centrifugation and biological replicates were pooled together by condition for processing in the 10X Genomics Chromium System. A targeted number of 10,000 cells were loaded for each experimental condition. Single cell mRNA sequencing libraries were prepared using the 10X Genomics Chromium Next GEM Single Cell 3' Library and Gel Bead Kit (v3.1) pipeline following manufacturer protocols.