There remains no effective treatment to reverse aging-related dementia disorders (ARDD), including Alzheimer?s disease (AD). Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with ARDD and AD and that vascular dysfunction leading to cerebral hypoperfusion is critical in the early stages of AD. Prior investigators showed that medin, a 50 amino acid peptide found in vascular smooth muscle layer, is the most common amyloid protein in humans with progressive vascular deposition with aging. Medin was implicated as a cause of vessel wall degenerative changes associated with vascular aging, but its role in aging-related cerebrovascular dysfunction is not known. We have preliminary data in both adipose and leptomeningeal arterioles that medin as well as ?-amyloid (A?), a peptide involved in AD, induce endothelial dysfunction through oxidative stress and reduced nitric oxide bioavailability and that medin induces strong pro- inflammatory response in endothelial cells. Our overall goal is to test the hypotheses that medin amyloid protein, alone or synergistically with A?, is a significant, but unrecognized, cause of ARDD by inducing human brain microvascular dysfunction and inflammation.
For Aim 1 we will probe the role of medin amyloid and its interaction with A? in causing aging-associated human cerebrovascular dysfunction and cognitive dysfunction. We will measure extent of cerebrovascular medin amyloidosis in the elderly and its relationship to cognitive dysfunction and Alzheimer?s disease using tissue and associated pre-mortem clinical data from Sun Health Research Institute Brain Donation Program. We will also probe mechanisms by which medin amyloid induces cerebrovascular dysfunction in ex-vivo rapid autopsy human brain leptomeningeal arterioles, focusing on the role of nitric oxide dysregulation, oxidative stress and induction of vascular inflammation. We will study the interaction between medin and A? in inducing human cerebrovascular dysfunction, vascular inflammation and cognitive dysfunction.
For Aim 2, we will validate whether peripherally obtained subcutaneous adipose arterioles are useful surrogates to brain cerebrovascular arterioles in studying medin and A?-induced microvascular dysfunction. The proposal will have impact in the potential discovery of a novel mechanism that could link vascular aging and cognitive dysfunction in the elderly. Furthermore, the use of a novel and unique human brain tissue model would enhance the translation relevance of the findings to the human condition.

Public Health Relevance

We still do not have any effective treatment for disorders that lead to dementia in the elderly such as Alzheimer?s disease (aging related dementia disorders or ARDD). It is now believed that problems with blood vessels supplying the brain may be important in causing the cognitive impairment of ARDD but the exact causes remain unknown. Medin is a common protein that accumulates with aging and it can misfold and cause amyloid deposits (insoluble protein accumulation) in blood vessels. We are testing whether medin is associated with cognitive impairment in the elderly by measuring medin in the brain blood vessels of brain donors and relating it to tests of cognitive function. We are also testing whether medin and beta-amyloid (A?), another amyloid protein implicated in Alzheimer?s disease, cause impaired function of brain blood vessels.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003767-01A1
Application #
9352441
Study Section
Neurobiology D (NURD)
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Phoenix VA Health Care System
Department
Type
Independent Hospitals
DUNS #
828729223
City
Phoenix
State
AZ
Country
United States
Zip Code
85012