ANG1-7 as an intervention for Alzheimer's Disease.

项目摘要 本研究的目的是评估口服副干酪乳杆菌对遗传的影响， 经修饰以表达阿尔茨海默病（AD）的血管紧张素（1-7）（LP-A）。目标1将检验以下假设： 病理学开始时的LP-A治疗将显著减缓或延迟pTau和Aβ标志物的积累 TgF 344-AD大鼠的炎症、去甲肾上腺素能轴突丢失和海马突触功能障碍， 依赖于Mas受体的激活。目的2将检验LP-A治疗改善 在TgF 344-AD大鼠中， 依赖于Mas受体的激活。预期影响：迄今为止，已证实的预防 缺乏年龄和AD介导的认知功能下降，因此对潜在有效干预措施的研究 迫切需要的。这项研究具有巨大的潜力，产生概念数据的证明，一个口头- 提供的干预改善或预防突触回路和认知功能的缺陷。这项工作是 重要的是，它解决了NIH认为至关重要的几个临床和公共卫生问题。 该项目的创新包括使用基因工程技术的概念方法， 益生菌形式的治疗化合物，以及为未来翻译奠定基础的研究设计 最终帮助解决AD相关认知能力下降的巨大健康负担。

PROJECT SUMMARY The objective of this study is to evaluate the impact of orally delivering Lactobacillus paracasei genetically modified to express Angiotensin (1-7) (LP-A) on Alzheimer’s Disease (AD). Aim 1 will test the hypothesis that LP-A treatment at the onset of pathology will significantly slow or delay accumulation of pTau and Aβ, markers of inflammation, loss of noradrenergic axons, and hippocampal synaptic dysfunction in TgF344-AD rats that is dependent upon activation of Mas receptors. Aim 2 will test the hypothesis that LP-A treatment improves performance in hippocampus-dependent behavioral assays and decreases anxiety in TgF344-AD rats that is dependent upon activation of Mas receptors. ANTICIPATED IMPACT: To date, proven treatments for preventing age- and AD mediated cognitive decline are lacking, thus research on potentially efficacious interventions is desperately needed. This study holds tremendous potential for generating proof of concept data that an orally- provided intervention improves or prevents deficits in synaptic circuit and cognitive function. The work is significant because it addresses several clinical and public health problems deemed critical by the NIH. Innovations in the project include the conceptual approach using genetic engineering techniques to deliver therapeutic compounds in probiotic form, and the study design which lays the groundwork for future translation to humans to ultimately help address the massive health burden of AD related cognitive decline.