Kynurenine Pathway Regulation of CNS Senescence in Alzheimer's Disease Pathology

这是一个NOT-AG-22-025行政补充申请的基础上，从我们的母公司非衍生的工作， 阿尔茨海默病（AD）奖R 01（AG 067510 - 01 A1），有可能提供初步数据证明 一份单独的AD重点R 01提交资料。我们最近发现并广泛发表了一个新时代- 相关的机制，驱动破坏骨稳态，似乎也适用于AD。具体地说， 作为犬尿氨酸（KYN）途径一部分的饮食衍生必需氨基酸色氨酸（TRP）代谢物 (KP)是由氧化损伤和炎症因子产生的。我们已经证明， KYN和其他KP代谢物在体外和体内阻断自噬，并诱导干细胞衰老， 单核细胞和破坏细胞和组织功能的成骨/肌肉细胞。衰老开始 被认为是AD发病机制中的关键效应子。关键的是，我们有初步数据显示，ROS和 炎症因子驱动星形胶质细胞和小胶质细胞的衰老，重要的是KYN负性地 影响人单核细胞衍生的小神经胶质细胞，包括诱导衰老标志物。衰老 并且肌肉骨骼组织中的衰老表型组织功能障碍可以通过阻断信号传导来挽救 途径的主要KP代谢物受体，芳烃受体（AhR），或通过抑制关键KP 产生KYN的吲哚胺2，3-双加氧酶（IDO）或犬尿氨酸单氧化酶（KMO） 产生其他CNS靶向KP代谢物。我们建议确定以金伯利进程为目标的适用性 在AD中驱动致病性衰老，部分最初使用快速（4-5个月）发展AD的5xFAD模型 病理重要的是，在临床试验中存在AhR、IDO-1和KMO的药理学抑制剂， 快速评估潜在的新型AD治疗方法。假设：衰老相关的氧化 应激/炎症导致KP介导的衰老细胞在大脑中的积累，这促进了衰老细胞的生长。 AD的发病机制和进展通过加剧淀粉样蛋白β（Aβ）诱导的神经毒性， tau病理学，和/或直接通过衰老CNS细胞功能障碍。本提案的初步数据 证明关键技术和概念方法的可行性将支持成功的AD R 01 应用程序.目标1.证明衰老标志物的大规模CyTOFF评估的可行性 与特定细胞类型标记共定位。这是识别KP特定模式的关键技术 介导的自噬抑制，以及CNS神经胶质、内皮细胞 和神经元细胞或其逆转与KP酶抑制。目标2。KP驱动衰老的评估 AD小鼠模型（5xFAD），可用于一年项目。将处理5xFAD和对照 与KP代谢物的子集或与AhR、IDO-1或KMO抑制剂。这将确定如果年龄和 ROS/炎症产生的KP代谢物介导衰老和AD病理学，并且如果抑制它们的代谢， 生产或信号传导阻断AD进展，导致新的近期治疗。

This is a NOT-AG-22-025 Administrative Supplement application based on work derived from our Parent non- Alzheimer’s disease (AD) award R01 (AG067510-01A1), that has potential to provide preliminary data justifying a separate AD focused R01 submission. We have recently identified, and extensively published, on a novel age- related mechanism that drives a disruption in bone homeostasis that appears to also apply to AD. Specifically, metabolites of the diet derived essential amino acid tryptophan (TRP) as part of the Kynurenine (KYN) Pathway (KP) are generated by oxidative injury and inflammatory factors. We have shown that the increased levels of KYN and other KP metabolites in vitro, and in vivo, block autophagy, and induce senescence in stem cells, monocytes, and osteogenic/muscle cells disrupting cell and tissue function. Senescence is beginning to be recognized as a key effector in AD pathogenesis. Critically, we have preliminary data showing that ROS and inflammatory factors drive senescence in astrocytes and microglial cells, and importantly that KYN negatively affects human monocyte derived microglial cells including the induction of senescence markers. Senescence and the aging-phenotype tissue disfunction in musculoskeletal tissue can be rescued by blocking the signaling pathway for the primary KP metabolite receptor, the Aryl Hydrocarbon Receptor (AhR), or by inhibiting key KP enzymes such as indoleamine 2,3-dioxygenase (IDO) that generates KYN, or kynurenine monooxidase (KMO) that generates other CNS targeting KP metabolites. We propose to determine applicability of targeting the KP driven pathogenic senescence in AD, in part initially using 5xFAD model that rapidly (4-5 months) develops AD pathology. Importantly, there are pharmacological inhibitors to AhR, IDO-1 and KMO in clinical trials supporting rapid assessment of potential novel AD therapeutic approaches. Hypothesis: Aging-associated oxidative stress/inflammation leads to KP mediated accumulation of senescent cells in the brain, which promote the pathogenesis and progression of AD via exacerbating amyloid beta (Aβ)-induced neurotoxicity and tau pathology, and/or directly via senescent CNS cell dysfunction. Preliminary data from this proposal demonstrating feasibility of key technical and conceptual approaches will support a successful AD R01 application. Aim 1. Demonstrate the feasibility of a large scale CyTOFF assessment of senescent markers co-localized with specific cell type markers. This is a key technology to identify specific patterns of KP mediated inhibition of autophagy together with the induction and spread of senescence in CNS glial, endothelial and neuronal cells or its reversal with KP enzyme inhibition. Aim2. Assessment of KP driven senescence in an AD mouse model (5xFAD) that can be used in a single year project. 5xFAD and controls will be treated with a subset of KP metabolites or with AhR, IDO-1 or KMO inhibitors. This will establish if age and ROS/inflammation generated KP metabolites mediate senescence and AD pathologies, and if inhibition of their production or signaling blocks AD progression, leading to novel near-term therapeutics.