Mechanisms of cognitive impairment caused by atherosclerosis and red blood cell released ATP

Project Summary With a fast pace of population aging, the prevalence of cognitive impairment and dementia including Alzheimer’s disease is expected to rise exponentially, placing an enormous social and economic burden worldwide. Epidemiologic and pathological studies have indicated an association between vascular diseases and cognitive

dysfunction, implicating vascular contributions to cognitive impairment and dementia (VCID). However, the driving pathologic mechanisms of VCID remain unclear, preventing the development of effective prevention and treatments. In response to the NIH Notice of Special Interest (NOT-HL-23-002): Promoting research to

understand VCID, this proposal aims to identify the mechanisms of cognitive impairment caused by atherosclerosis and red blood cell (RBC) released ATP using both animal models and human samples. Atherosclerosis is the leading cause of vascular disease worldwide, yet the role of atherosclerosis in cognitive

impairment and the underlying mechanisms remain largely unknown. Our study using high fat diet (HFD)-fed ApoE-/- mice showed that atherosclerotic plaques extensively blocked carotid and intracranial arteries, resulting in brain hypoperfusion, cerebrovascular remodeling and neuroinflammation. Importantly, cognitive behavior tests

detected significant memory deficits in ApoE-/- mice as early as 12 weeks with HFD, but not in age matched mice with normal diet, demonstrating a causal relationship between atherosclerosis and cognitive impairment. Our study also showed that disturbed blood flow-triggered ATP release from RBCs via pannexin 1 channel (Panx1)

contributes significantly to the initiation and progression of atherosclerosis as well as cognitive impairment. Specifically, Panx1 deletion from RBCs led to reductions of plaque formation and alleviations of the cognitive deficit in HFD-fed ApoE-/- mice. Additionally, we showed that hypercholesterolemia enhances vascular

endothelial cell (EC) [Ca2+]i responses to ATP, a key signaling for EC barrier dysfunction. These findings led to our central hypothesis that atherosclerosis-induced brain hypoperfusion and vascular inflammation via hypercholesterolemia along with RBC-released ATP are the key risk factors of atherosclerosis-driven cognitive

impairment. Three specific hypotheses will be tested experimentally in vivo, in vitro, and computationally in silico under three specific aims. Aim 1: The atherosclerotic blockage of carotid and intracranial arteries causes brain hypoperfusion and cerebrovascular remodeling, resulting in cognitive impairment. Aim 2: RBC-released ATP

contributes significantly to atherosclerosis-induced cerebrovascular pathology as well as the onset and progression of cognitive impairment. Aim 3: Hypercholesterolemia and hemodynamic alteration-induced RBC released ATP are the key risk factors synergistically contribute to atherosclerosis induced cerebrovascular

inflammation and EC barrier dysfunction in mice and humans. The new knowledge gained from this study will advance our understanding of the risk factors and mechanistic insight into atherosclerosis-induced VCID and hence promote early treatment and lifestyle interventions to prevent or delay the onset of cognitive decline.