Title : Essential roles, mechanisms and consequences of vascular dementia
Abstract:
Vascular contributions to cognitive impairment and dementia (VCID) is a common neurodegenerative disease. This dementia includes all types of vascular dementia. It is caused by brain cerebral blood vessel dysfunctions. VCID has high morbidity and mortality. Diabetes is a leading factor in VCID. However, the essential roles, mechanisms and consequences of VCID are still largely unknown. Moreover, the current treatments for VCID are neither very specific nor effective. Dysfunctions of cerebral arteries (CAs) may cause blood hypoperfusion to the brain and then makes an important contribution in the initiation and progress of 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. The cell calcium signaling is primarily determined by ion channels on the plasma membrane and sarcoplasmic reticulum (SR) membrane. Therefore, we have started to explore whether and which ion channels might be essential for diabetes-evoked VCID. Consistent with previous reports by us and other investigators, we have found that intraperitoneal injection of streptozotocin caused a large increase in blood glucose, leading to diabetes in mice. A series of our studies have also discovered that the diabetic mice had declined cognition, impaired memory, and increased anxiety, thereby exhibiting significant VCID. This diabetic vascular 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 novel essential role in the development of diabetes-caused VCID; presumably, specific pharmacological and genetic inhibition of RyR2 and/or stabilization of FKBP12.6 in vascular SMCs may become specific and effective treatment options for diabetic VCID.
