THE ROLE OF INFLAMMASOME ACTIVATION IN A CHRONIC CEREBRAL HYPOPERFUSION MOUSE MODEL OF VASCULAR DEMENTIA - FROM PATHOPHYSIOLOGY TO TREATMENTS

Abstract

Chronic cerebral hypoperfusion (CCH) contributes to vascular cognitive impairment (VCI) via complex molecular and cellular pathways. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of CCH to investigate its effect on the innate immune response—particularly the inflammasome signalling pathway in VCI. Comprehensive analyses revealed that CCH induces activation of inflammasome signalling pathway, cell deaths, glial-cell activation, white-matter lesion and hippocampal neuronal loss. Moreover, in AIM2-knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, cell deaths, as well as resistance to microglial activation, myelin breakdown, hippocampal neuronal loss, and cognitive deficits following BCAS. Hence, we demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of CCH-induced brain injury and therefore represent a promising therapeutic target for attenuating cognitive impairment in VCI. We also identified intermittent fasting as a potential treatment as it attenuates the inflammasome-associated cell deaths in the brain following CCH.