Impact of Wnt7a on Mast Cell-mediated inflammation associated with Alzheimer's Disease.

总结 阿尔茨海默病（AD）是老年人痴呆和残疾的最常见原因， 在美国，AD病理学特征的主要死因包括： 海马中的神经毒性淀粉样蛋白β（Aβ）和tau蛋白缠结。唯一一种FDA批准的AD疾病 修饰药物，一种抗Aβ抗体（Aducanumab），对认知的益处非常有限。因此， 迫切需要开发针对AD的其他疗法。有趣的是，Aβ斑块也存在于健康人群中， 提示单独的Aβ不足以诱发AD。最近的一项研究表明， AD是神经炎症和Aβ斑块/tau缠结的存在。 肥大细胞（MC）是AD中增加的主要类型的免疫细胞。MC对于煽动和 持续的炎症这是因为MC可以储存大量的炎症介质（例如，TNFα， 组胺、类胰蛋白酶），其可在活化后数分钟至数小时内释放， MC对其他免疫细胞具有快速和强烈的影响。MC重要性的直接证据 AD中的神经炎症来自于将MC活化抑制剂crologyn注入小鼠的研究， 海马，以及早期临床试验，其中MC抑制剂马赛替尼导致认知益处 在AD患者中。然而，在AD神经炎症的背景下，MCs的调节剂在很大程度上仍然难以捉摸。 wnt 7a是海马神经发生的重要信号分子。然而， 关于Wnt 7a在AD期间MC介导的炎症中的作用。父R 01研究Wnt 7a作为关键因素 通过调节关节炎症，它是发展骨关节炎倾向的看门人。在这 作为补充建议，我们将扩大Wnt 7a对MC介导的炎症的作用的研究。 与AD相关，利用父R 01的资源和跨学科团队的专业知识。在我们 初步研究发现，神经毒素Aβ1-42可显著诱导MC活化，并诱导异位Wnt 7a表达， 强烈抑制MC活化。因此，我们假设Wnt 7a抑制Aβ1-42诱导的MC活化， 从而减少与AD进展相关的神经炎症。我们将通过调查来验证这一假设 Wnt 7a是否是抑制淀粉样蛋白β诱导的MC活化所必需和充分的，以及Wnt 7a通过哪些途径 在这个过程中采取行动。 本研究的新奇在于研究AD背景下MC激活的调节， 这在很大程度上是未知的。这将对认识AD的发病机制产生深远的积极影响。以来 骨关节炎关节中的MC也强烈增加，本研究也将属于母体范围 R 01用于研究Wnt 7a对MC炎症的作用。因此，本研究对这两个领域都具有重要意义 AD和骨关节炎的研究。

SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia and disability in the elderly and the sixth leading cause of death in the U.S. Signature AD pathology includes the presence of protein aggregation of neurotoxic amyloid-beta (Aβ) and tau tangles in the hippocampus. The only FDA-approved AD disease- modifying drug, an antibody against Aβ (Aducanumab), has very limited benefit on cognition. Thus, there is an urgent need to develop additional therapies for AD. Interestingly, Aβ plaques are also found in healthy people, suggesting that Aβ alone is not sufficient to instigate AD. A recent study indicated that the strongest predictor for AD is the presence of both neuroinflammation and Aβ plaques/tau tangles. The mast cell (MC) is a major type of immune cells that is increased in AD. MCs are critical for instigating and perpetuating inflammation. This because MCs can store large amounts of inflammatory mediators (e.g., TNFα, histamine, tryptase) in their granules, which can be released within minutes to hours upon activation, enabling MCs to have a fast and strong impact on other immune cells. Direct evidence of MC’s importance in neuroinflammation in AD comes from the mouse study of infusing cromolyn, an inhibitor of MC activation, into the hippocampus, as well as from early-stage clinical trials, where MC inhibitor Masitinib led to cognitive benefits in AD patients. However, regulators of MCs in the context of AD neuroinflammation remain largely elusive. Wnt7a is an important signaling molecule controlling neurogenesis in the hippocampus. However, little is known about the role of Wnt7a in MC-mediated inflammation during AD. The Parent R01 investigates Wnt7a as a critical gatekeeper toward a propensity to develop osteoarthritis for its modulation of joint inflammation. In this Supplemental proposal, we will extend the investigation of the role of Wnt7a towards MC-mediated inflammation relevant to AD, capitalizing on the resources of the Parent R01 and expertise of an interdisciplinary team. In our preliminary study, we discovered that neurotoxic Aβ1-42 significantly induced MC activation, and ectopic Wnt7a strongly inhibited MC activation. Thus, we hypothesize that Wnt7a inhibits MC activation induced by Aβ1-42, thereby reducing neuroinflammation associated with AD progression. We will test this hypothesis by investigating whether Wnt7a is necessary and sufficient to inhibit amyloid β-induced MC activation and which pathways Wnt7a act through in this process. The novelty of this study lies in the investigation of the regulation of MC activation in the context of AD, an area that is largely unknown. It will have a profound and positive impact on the understanding AD pathogenesis. Since MCs are strongly increased in osteoarthritis joints as well, this study will also fall within the scope of the parent R01 for investigating the role of Wnt7a on MC inflammation. Thus, this work is highly significant to both the fields of AD and osteoarthritis research.