AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia

Abstract

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long term cognitive impairment and memory loss. Inflammasome is an intracellular multi-protein complex that initiates an innate immune response, and is involved in multiple acute and chronic neurological diseases such as ischemic stroke, Alzheimer's disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). While evidence for direct involvement of the inflammasome complex in VaD is lacking, a cytokine profile of plasma from VaD patients found IL-1β to be the most abundant.Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the effect of chronic cerebral hypoperfusion on the inflammasome signaling pathway. To further examine the functional role of AIM2 inflammasome activation on injury following chronic cerebral hypoperfusion, mice with AIM2 deficiency (AIM2 KO) were studied.Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 KO mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS.Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.