The prevalence of dementia is expected to triple by 2050 making it a major threat to world public health. Vascular dementia makes up 20% of dementia cases and vascular causes contribute to another 30%. These vascular contributions to cognitive impairment and dementia are known by the acronym VCID. There is no known effective treatment for VCID; however observational studies strongly suggest that physical exercise is effective at reducing progression of cognitive decline and dementia. Chronic remote ischemic conditioning (C-RIC), is the repetitive inflation and deflation of a blood pressure cuff on the limbs for periods of weeks or months and may be an ?exercise mimetic?. Our data in the VCID mouse model shows that C-RIC is cerebroprotective, increasing cerebral blood flow and collateral remodeling and improving cognition. Our central hypothesis is that C-RIC triggers a cerebroprotective phenotype by activation of peripheral limb AMPK? and eNOS with an increase in circulating plasma nitrite and ?endocrine NO activity? leading to increased CBF, angiogenesis, and collateral remodeling. Our sub-hypothesis is that these effects of C-RIC are age and sex independent.
Our Specific aims are:
Aim 1 : Determine the critical role of eNOS in mediating C-RIC induced cerebroprotection and vascular remodeling upon eNOS.
Aim 2 : Determine the dependence of C-RIC cerebroprotection upon endothelial- specific AMPK?1, an upstream regulator of eNOS. We will utilize an endothelial specific AMPK? mouse knockout (KO) model to determine whether RIC?s protection is dependent upon endothelial AMPK?1.
Aim 3 : Determine the role of bone marrow (BM) -derived cells in C-RIC-induced angiogenesis and collateral remodeling. eNOS in BM cells may be critical to the mechanism of C-RIC. These studies will help us to define the mechanism of C-RIC in cerebroprotection and help us translate C-RIC from the bench to the bedside in patients with VCID to reduce dementia.
Vascular contributions to dementia and cognitive impairment (VCID) is common and contributes to about half of the cases of dementia. We have developed an intervention called ?chronic remote ischemic conditioning? (C-RIC) where we repeatedly inflate and deflate a blood pressure cuff on the limbs and this is very effective in a mouse model of VCID. We find that C-RIC increases new blood vessel formation in the brain and improves cognition. In this proposal, we will determine the mechanism of action by which C-RIC improves blood vessel formation and cognition. C-RIC is a simple and safe therapy that could help reduce dementia.
| Vaibhav, Kumar; Braun, Molly; Khan, Mohammad Badruzzaman et al. (2018) Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation. J Exp Med 215:2636-2654 |
