Cerebral Arteriole Structure/Function in Diabetic Ischemic Brain Injury

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Over half of the 5.8 million Americans who suffer from dementia have Vascular contributions to Cognitive Impairment and Dementia (VCID), for which there are NO effective treatments. The focus on neuronal pathologies of the disease limited our understanding of the cellular/molecular mechanisms that promote the onset and progression of cognitive decline at the neural-glial-vascular (NGV) interface and stalled the development of any effective therapeutic strategies. While it is known that diabetes increases the risk and severity of VCID, the inadequate integration of diabetes experimental VCID research has widened this vast knowledge gap. The specific objective of this renewal proposal is to address these gaps by defining cellular mechanisms contributing to the progressive disruption of the NGV unit using diabetes and stroke as disease models. While neurological diseases have long been categorized as vascular, neurodegenerative or inflammatory, it is now recognized that these mechanisms are interwoven. Our exciting findings in the past funding period led us to focus on the mechanisms of complex interaction within the NGVU: 1) diabetic male and female rats display cognitive deficits that are worsened after stroke and accompanied by exhibit extensive remodeling at the NGV interface, 2) cells that survive initial injury lose their neurotrophic/proangiogenic properties and become inflamed in both sexes, 3) mature brain derived neurotrophic factor (mBDNF) is decreased while proapoptotic proBDNF & its cognate receptor p75NTR are increased in the diabetic brain and brain microvascular endothelial cells (BMVECs), 4) unlike control rats that show a dynamic switch between anti/pro-inflammatory microglia after stroke, diabetic rats display sustained proinflammatory microglia and microglia knockdown in the early poststroke period improves sensorimotor and cognitive outcomes, 5) endothelial expression of senescent markers is amplified in diabetic rats after ischemic injury, 6) interleukin-1 (IL-1), its receptor and phosphorylated tau (p~tau) are increased in BMVECs under inflammatory stress, and 7) cilostazol, a clinically approved vasodilator with senostatic/anti-inflammatory properties that is on current clinical trials for the prevention of progressive cognitive impairment in stroke survivors, improves endothelial inflammation as well as cognition in diabetic rats. Two aims with translational and mechanistic studies will test the central hypothesis is that diabetes-mediated premature endothelial senescence promotes vasotrophic uncoupling and endothelial tau pathology, collectively propagating senescence-associated inflammation within the NGVU after brain injury leading to progressive VCID. Aim 1 will determine the causal role of endothelial (e)senescence in progressive VCID in diabetes by defining a) a) the impact of cell specific inhibition of senescence via endothelial (e)p16 knockdown or intranasal delivery of cilostazol in VCAM1-tagged nanoparticles on the evolution of NGVU senescence/dysfunction and cognitive deficits using innovative Hyperion imaging mass cytometry and complex automated behavior analyses; b) tempora/spatial development of e- inflammation using ultra-sensitive VCAM1-tagged molecular magnetic resonance imaging (mMRI); c) the comparative impact of cilostazol on cognitive decline in both sexes; and d) the most effective tactics by which elimination of e-senescence improves VCID. Aim 2 will determine the mechanisms by which e-senescence drives NGVU senescence by defining a the role(s) of dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IL1R1-mediated p~tau and mBDNF decrease; b) the impact of endothelial IL1R1 silencing on cognitive deficits; and c) the impact of e-senescence on NGVU senescence and functions using creative media transfer experiments. Given that Veterans disproportionately suffer from cardiometabolic risk factors and VCID, identification of innovative and effective mechanism-based therapeutic approaches that would prevent, retard and/or dampen the onset and progression of cognitive impairment, including a rapidly translatable senostatic therapy by repurposing of cilostazol, will have a significant impact on human health and the VA mission.