Project Summary Current US demographic trend indicates that age-related dementia is becoming a serious public health crisis. Its prevalence and severity is expected to increase substantially in the near future. Currently, neurodegenerative diseases lack effective treatments. Therefore, understanding the processes that contribute to these diseases is needed for the design of effective and preventive treatment measures. Significant decrease in cerebral blood flow (CBF) is a major hemodynamic alteration leading to neurodegeneration and age-related cognitive decline. Nitric Oxide (NO)-dependent vasomotor reactivity of cerebral arterioles plays a central role in regulation of cerebrovascular hemodynamics and adequate brain blood perfusion. The majority of beneficial effects of NO are mediated via its receptor, soluble Guanylyl Cyclase (sGC). Age-dependent decline of NO/cGMP signaling underlies impaired ability of patients with a wide range of neurodegenerative diseases to learn and process new information. However, the molecular mechanisms contributing to sGC deactivation in these cases are poorly understood. Oxidation or loss of sGC-bound heme contributes to the decline of NO-sGC function and leads to sGC protein degradation. Our Preliminary data indicate that loss and oxidation of sGC heme is one of the factors associated with aging. We therefore propose that oxidation-induced loss of sGC heme negatively affects the regulation of CBF and exacerbate the decline of neurologic and cognitive functions with aging. Therefore, augmenting sGC function by supporting heme metabolism or applying heme- independent sGC activators should prevent/delay age-related decline in CBF and associated neurologic, memory, and cognitive functions. If proven, our hypothesis will stimulate the development of new therapeutics targeting cerebrovascular dysfunctions. There will be two Specific Aims: Aim 1 will determine how changes in oxidative state of sGC-bound heme affect CBF and cognitive functions in ageing mice. Aim 2 will establish the effect of heme- and sGC-targeting interventions on the age- dependent decline of sGC function in brain. Our data will provide empirical evidence that the integrity and redox state of sGC heme is essential for regulation of CBF and contributes to the decline of neurological/cognitive function. We also aim to provide proof for the principle that pharmacological and dietary countermeasures targeting heme-deficient sGC in cerebral vasculature will alleviate neurodegeneration and improve cognitive decline.