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

摘要 阿尔茨海默病(AD)是导致老年人痴呆和残疾的最常见原因，在老年人中占第六位 美国标志性AD病理中的主要死因包括存在蛋白质聚集 神经毒性淀粉样β蛋白(Aβ)和tau蛋白在海马体中缠绕在一起。FDA批准的唯一AD疾病- 修饰药物是一种抗Aβ的抗体(Aducanumab)，对认知的益处非常有限。因此，有一个 迫切需要为AD开发更多的治疗方法。有趣的是，在健康人中也发现了Aβ斑块， 这表明Aβ本身并不足以引发AD。最近的一项研究表明，对 AD是指同时存在神经炎症和Aβ斑块/tau缠结。 肥大细胞(MC)是一种主要的免疫细胞类型，在AD时会增加。MCS对于煽动和 使炎症持续存在。这是因为MC可以存储大量的炎症介质(例如，肿瘤坏死因子α， 组胺、类胰蛋白酶)，激活后可在几分钟至几小时内释放，使 MCS对其他免疫细胞产生快速而强烈的影响。MC的重要性的直接证据 阿尔茨海默病的神经炎症来自小鼠向脑内注射色甘露，一种MC激活的抑制剂， 海马体，以及来自MC抑制剂Masitinib导致认知益处的早期临床试验 在AD患者中。然而，在AD神经炎症的背景下，MC的调节机制在很大程度上仍然难以捉摸。 WNT7a是控制海马区神经发生的重要信号分子。然而，人们对此知之甚少 关于Wnt7a在阿尔茨海默病MC介导的炎症中的作用。父R01将WNT7a调查为关键 看门人有患骨关节炎的倾向，因为它对关节炎症有调节作用。在这 补充建议，我们将扩大WNT7a在MC介导的炎症中的作用的研究 与AD相关，利用母公司R01的资源和跨学科团队的专业知识。在我们的 初步研究发现，神经毒性Aβ1-42可显著诱导MC活化，且异位Wnt7a 强烈抑制MC的激活。因此，我们假设WNT7a抑制Aβ1-42诱导的MC激活， 从而减少与AD进展相关的神经炎症。我们将通过调查来检验这一假设 Wnt7a是否是抑制淀粉样蛋白β诱导的MC激活的必要条件和充分条件，以及Wnt7a通过哪些途径 在这个过程中全力以赴。 本研究的创新之处在于研究了阿尔茨海默病患者脑区MC激活的调控。 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而积极的影响。自.以来 MCS在骨关节炎关节中也有较强的增加，本研究也属于家长的研究范围 R01用于研究WNT7a在MC炎症中的作用。因此，这项工作对这两个领域都具有重要意义 阿尔茨海默病和骨关节炎的研究。

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.