Cerebral parenchymal arteriole dysfunction and cognitive decline in a life-long high fat feeding model

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Abstract Obese/overweight patients have an increased risk of developing cognitive impairments that can lead to dementia. This is a major public health concern because the majority of the adult population is overweight or obese. Overweight individuals have reduced cerebral perfusion and this can cause impaired cognition; the cause of this cerebral hypoperfusion is unknown. This is an important knowledge gap; understanding the cause of the hypoperfusion is key to identifying therapeutic targets to slow or prevent cognitive decline in a society plagued by obesity. The parenchymal arterioles (PAs) connect the pial and capillary networks and regulate the perfusion of the brain parenchyma. Our preliminary data show that endothelium dependent dilation is markedly impaired in PAs from overweight rats and these rats develop cognitive dysfunction. Despite their importance in regulating brain perfusion, little is known about PA function in health and disease. Dilation in PAs relies heavily on intracellular calcium (Ca2+) signaling, and Ca2+ influx through transient receptor potential (TRP) channels is an important mediator of cerebral artery endothelium dependent dilation. We showed that activation of the vanilloid 4 TRP channel (TRPV4) causes PA dilation. Preliminary studies show that TRPV4 expression is reduced in overweight rats and this is linked to mineralocorticoid receptor activation. Circulating levels of the mineralocorticoid aldosterone are increased in overweight patients and in our rat and mouse models. Our hypothesis is that MR activation in PA endothelial cells leads to reduced TRPV4 expression, impaired endothelium-dependent dilation, cerebral hypoperfusion and cognitive impairment in overweight rats. We will utilize a combination of in vivo and in vitro techniques including MRI, confocal microscopy, electrophysiology and pressure myography to test our hypothesis. We will determine how excess adiposity impairs PA function, cerebral perfusion, and cognition. Our working hypothesis is that TRPV4 expression is reduced in overweight rats and that this leads to impaired Ca2+-mediated endothelium-dependent dilation in PAs and is associated with reduced cerebral perfusion and impaired cognition. We further propose that directly inhibiting TRPV4 will cause cerebral hypoperfusion and cognitive decline. We will also determine the effects of MR activation on PA function, cerebral perfusion, and cognition. Our working hypothesis is that MR activation in PA endothelial cells causes reduced TRPV4 expression, impaired Ca2+ mediated dilation, cerebral hypoperfusion and cognitive decline. We further propose that MR antagonism in overweight rats will improve PA function in a TRPV4 dependent manner and that this will lead to improved cerebral perfusion and cognitive function. The MR is a highly drugable target, MR antagonists are safe, effective FDA approved drugs. Their use in the overweight/obese population could dramatically reduce the burden on families and the healthcare system that occurs when patients become too cognitively impaired to live independently.