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

据估计，阿尔茨海默病(AD)影响了500多万美国人。越来越多的证据表明 血管病变和功能障碍在认知障碍、临床阿尔茨海默病和痴呆中起关键作用。 因此，任何改善血管病变的策略在治疗上都是非常有吸引力的。在 父母建议，我们提出腺苷琥珀酸(AdSucc)是一种脑内源性促血管生成因子。在……里面 目前的建议，我们假设AdSucc介导的脑血管生成随着年龄的增长而下降，因此 导致与年龄相关的脑血管改变，并导致功能障碍，包括AD样 病理学。在家长奖的当前第二个预算年度收集的数据有力地支持了我们的 新的AdSucc促血管生成机制。我们发现在低脑压下，AdSucc显著增加 能量调节和促进脑血管生成来补偿这些条件。然而，我们 意外发现AdSucc在衰老小鼠的产量下降，表明AdSucc血管生成 机制功能障碍可能导致与年龄相关的脑血管改变，从而导致认知功能障碍 损害和痴呆症，包括阿尔茨海默病。然而，这一初步观察还需要进一步系统化 验证，使我们的行政补充请求合理化。我们的中心假设将通过 父级奖项现有具体目标的以下次级目标： 1.确定在低能量条件下衰老小鼠的AdSucc产量是否减少 2.确定AdSucc治疗是否降低了老龄小鼠的血管生成反应 3.确定AdSucc产生减少是否会导致AD样病理 实现这些子目标将把我们的AdSucc介导的脑血管生成的新机制与 阿尔茨海默病的发展及其对认知障碍和痴呆症的贡献。这一点意义重大 因为如果成功，它将验证一种新的机制，并勾勒出治疗这些疾病的新的潜在靶点 基于父母奖中提出的新型AdSucc介导的脑血管生成的病理学。这个 该项目具有创新性，因为它解决了以前未被认识到的大脑信号机制 血管生成并为年龄相关的血管损伤和痴呆建立了一种新的机制， 包括公元。拟议的工作在父奖项的范围内，因为两个项目都涉及 相同新的AdSucc机制在相同低能量下对脑血管生成的贡献 条件，而行政补编将父项目扩大到包括更多的老年人 老鼠的数量。

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.