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

这是一份NOT-AG-22-025行政补充申请，基于我们的母公司非

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.