Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain

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Alzheimer's disease (AD) is estimated to affect over 5 million Americans. There is growing evidence showing that vascular pathologies and dysfunction play a critical role in cognitive impairment, clinical AD, and dementia. Therefore, any strategy to ameliorate vasculature pathology is extremely attractive therapeutically. In the parent proposal, we proposed that adenylosuccinate (AdSucc) is a brain endogenous pro-angiogenic factor. In the current proposal, we hypothesize that AdSucc-mediated brain angiogenesis declines with age, thus contributing to age-related changes of the cerebrovasculature and causing functional deficits, including AD-like pathology. Data collected during the current second budget year of the parent award strongly support our novel AdSucc pro-angiogenic mechanism. We found that AdSucc is significantly increased under brain low energy conditions and promotes brain angiogenesis to compensate for these conditions. However, we unexpectedly discovered that AdSucc production declines in aged mice, indicating that AdSucc angiogenic mechanism dysfunction might contribute to age-related alterations in cerebral vasculature and thus cognitive impairment and dementia, including AD. However, this preliminary observation needs further systematic validation, rationalizing our administrative supplement request. Our central hypothesis will be tested via the following sub-aims of the existing specific aims of the parent award: 1. Determine if AdSucc production is decreased in aged mice upon low energy conditions 2. Determine if angiogenic response to AdSucc treatment is decreased in aged mice 3. Determine if decreased AdSucc production results in AD-like pathology Fulfilling these sub-aims will link our novel mechanism for AdSucc-mediated brain angiogenesis to the development of Alzheimer's disease and its contribution to cognitive impairment and dementia. It is significant because if successful, it will validate a novel mechanism and outline new potential therapeutic targets for these pathologies based on the novel AdSucc-mediated brain angiogenesis proposed in the parent award. The project is innovative because it addresses a previously unrecognized signaling mechanism for brain angiogenesis and establishes a novel mechanism for age-related vasculature impairments and dementia, including AD. The proposed work is within the scope of the parent award as both projects address the contribution of the same novel AdSucc mechanism to brain angiogenesis under the same low energy conditions, while the administrative supplement extends the parent project to include additional elderly populations of mice.