Promising novel therapeutic strategies for vascular Dementia

Title : Promising novel therapeutic strategies for vascular Dementia

Abstract:

Vascular dementia (VD) has high morbidity and mortality. Diabetes is a leading factor for VD. The cellular responses and signaling mechanisms for diabetes-induced VD are largely unknown, and the current treatments for VD are neither very specific nor effective. Dysfunctions of cerebral arteries (CAs) to cause blood hypoperfusion to the brain makes an important contribution in VD. Perfusion of CAs is predominantly generated and controlled by contraction and relaxation of smooth muscle cells (SMCs). These two cellular processes are fundamentally produced and regulated by cell calcium signaling. 
We have started to explore whether and which ion channels might be essential for diabetes-evoked VD. Consistent with the previous reports, we have found that intraperitoneal injection of streptozotocin caused a large increase in blood glucose, leading to diabetes in mice. The diabetic mice had declined cognition, impaired memory, and increased anxiety, thereby exhibiting significant VD. This dementia might occur due to cerebral vasoconstriction and subsequent blood hypoperfusion, as revealed by Laser Speckle Imaging System. Diabetic cerebral vasoconstriction could result from increased intracellular calcium concentration ([Ca²⁺]_i) in CASMCs. Increased [Ca²⁺]_i was attributed to the augmented Ca²⁺ release from the SR, the major intracellular Ca²⁺ store, which followed the hyperfunctional activity of type-2 ryanodine receptor (RyR2), the calcium release channel on the SR in CASMCs. Biochemical and genetic experiments indicated that the hyperfunction of RyR2 channel was a result of dissociation of FK506 binding protein 12.6 (FKBP12.6), an endogenous channel stabilizer (or inhibitor). Excitingly, we have further found that exposing VSMCs and isolated mitochondria to increased free calcium concentrations resulted in a proportional increase in ROS generation. Equally importantly, ROS generation in isolated cells, mitochondria and mitochondrial complex III from CASMCs were all increased in diabetic mice. DNA damage and Tau phosphorylation in CASMCs were largely increased as well.
In conclusion, our findings provide the first evidence that diabetes causes RyR2/FKBP12.6 dissociation, increases RyR2 activity and calcium release, mitochondrial calcium increase and ROS production, DNA damage, and Chk2 phosphorylation in CASMC, thereby leading to vascular dementia; presumably, our results further demonstrate that specific pharmacological and genetic RyR2 inhibition, FKBP12.6 stabler, mitochondrial ROS inhibitors and removers in vascular SMCs may become specific and effective treatments for diabetic VD and vascular complications.

Biography:

Dr. Yong-Xiao Wang has been a Full Professor in Department of Molecular and Cellular Physiology at Albany Medical College since 2006. Dr. Wang obtained his MD at Wannan Medical University, PhD at Fourth Military Medical University, and postdoctoral training at Technology University of Munich and University of Pennsylvania. He has made many important findings using complementary molecular, biochemical, physiological, and genetic approaches at the molecular, organelle, cellular, tissue and organism levels in animals and human samples, had numerous publications in Nature Commun (impact factor: 14.290), Antioxid Redox Signal (8.209), Proc Natl Acad Sci USA (9.432), Nature (34.480), Circ Res (9.214), and other highly peer-reviewed journals and academic books, and served as the editorial board member and/or section editor as well as the executive committee member and/or subcommittee chair for professional societies.