Novel important cellular responses, signaling mechanisms and therapeutic options in vascular dementia

Title : Novel important cellular responses, signaling mechanisms and therapeutic options in vascular dementia

Abstract:

Vascular contributions to cognitive impairment and dementia (VCID) have high morbidity and mortality, and diabetes is a leading factor for VCID. The signaling mechanisms for diabetes-induced VCID are largely unknown, and the current treatments for VCID are neither very specific nor effective. Dysfunctions of cerebral arteries (CAs) to cause blood hypoperfusion to the brain makes an important contribution in VCID. 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 VCID. 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 VCID. 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). In conclusion, our findings provide the first evidence that RyR2/FKBP12.6 dissociation exerts a crucial role in the development of diabetes-caused VCID; presumably, specific pharmacological and genetic inhibition of RyR2 and/or FKBP12.6 stabler in vascular SMCs may become specific and effective treatment options for diabetic VCID and vascular complications.

Audience Take Away Notes:

• Our current presentation will greatly help the audience to create their future research directions
• The finding presented may significantly assist the audience to develop novel preventive and therapeutic strategies for VCID and other dementias.
• Our research could also be used by other faculty to expand their research or teaching.

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.