Cerebral vascular calcium signaling in diabetic Alzheimer's disease-related dementias - Alzheimer's disease (AD) and AD-related dementias (ADRD) are the common incurable neurodegenerative even conditions characterized by progressive cognitive deterioration, memory decline and death. The major forms of ADRD include vascular contributions to cognitive impairment and dementia (VCID). In agreement, vascular dementia is the second most common form of dementia and the most frequent comorbidity with AD. Diabetes may production is a leading factor in the development of VCID; the ole of diabetes primarily occur due to the abnormal glucose metabolism and i ncreased reactive oxygen species (ROS) in cerebral vascular smooth muscle cells (CASMCs) r . In support, antioxidant therapies have shown promising results in protecting against diabetes-induced VCID and other dementias. the molecular mechanisms that link diabetes to the development of VCID remain to be elucidated, and current treatments for these diseases are neither always effective nor specific. The Based on our preliminary findings with previous work, in this project, we propose a novel central hypothesis that diabetes increases Rieske iron-sulfur protein (RISP)-mediated mitochondrial ROS, dissociates FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) to remove its inhibitory effect on RyR2 channel and induce Ca2+ release, which causes cerebral vasoconstriction and cerebral blood flow reduction, thereby leading to progressive memory loss, cognitive decline and VCID. To test this exciting hypothesis, we will conduct a series of mechanistic studies primarily by employing smooth muscle-specific RISP, RyR2, and FKBP12.6 knockout (KO) and/or overexpression (OE) mice with other complementary advanced experimental approaches to address the following specific questions (Specific Aims): Aim 1: Are the increased RISP-mediated mitochondrial ROS in CASMCs essential for VCID induced by diabetes? Aim 2: Is RyR2/FKBP12.6 complex dissociation a key consequence for the increased RISP-mediated mitochondrial ROS to mediate VCID induced by diabetes? The objectives of the present proposal are not only to enhance our understanding of the molecular mechanisms for VCID, ADRD devastating diseases. and AD, but also help to identify novel therapeutic targets for these common
