Drug repurposing for Alzheimer’s disease-related inflammation caused by a TBI

项目总结/摘要 疾病预防控制中心估计，至少有20万美国老年人（> 65岁）将有创伤性脑损伤（TBI） 每年，主要由跌倒引起的闭合性头部损伤（CHI）引起。老年痴呆症患者的大脑 神经病理改变，具有明显的反应性小胶质细胞和星形胶质细胞等标志物， 神经炎症获得性脑损伤可进一步加剧这种反应性神经胶质增生状态， 神经炎症阿尔茨海默病提出了一个重大的治疗挑战，因为病理学可以 发展了几十年。然而，我们认为，防止恶化是一个可以实现的治疗目标， 在那些有患阿尔茨海默病风险的人中，由后天性脑损伤引起的神经炎症。 控制老年人TBI后的神经炎症是改善患者预后的一种有希望的途径。 结果。然而，没有药物获得FDA批准用于轻度TBI的特定用途。也有有限的 有证据指导FDA批准的靶向神经炎症的药物的再利用， 人口广谱免疫抑制剂是不可取的，而选择性生物制剂（如 抗肿瘤坏死因子）是有希望的，他们也有增加感染的风险，这是一个问题，在老年人 成年人有感染的危险。我们的目标是确定靶向免疫调节（不是， 免疫抑制剂），具有较高的获益风险比。我们最近发现了 抗生素阿奇霉素（AZM）作为一种免疫调节剂，具有脊髓神经保护作用 损伤由于其安全性，AZM经常被规定为几种疾病的预防性治疗。 条件并在高危疾病人群中广泛使用。该提案旨在提供证据- AZM作为一种安全有效的神经炎症调节药物的主要数据。我们将测试中央 假设AZM可以改变CHI后的神经炎症并改善认知结果， APP/PS1 KI小鼠模型的阿尔茨海默病相关病理学有以下两个具体目的（SA）。 SA 1：确定AZM在8月龄APP/PS1 KI小鼠中的免疫调节剂量依赖性效应 模型遵循CHI。 SA 2：评价AZM对CHI-induced行为和阿尔茨海默病相关的影响。 8月龄APP/PS1 KI小鼠的神经病理学。 这项概念验证研究可以确定AZM是一种安全且耐受性良好的FDA批准的药物， 在CHI之后，脆弱的老年大脑的损伤和恢复速度。一旦AZM治疗的可行性 已经建立，新的药物开发和临床研究领域的潜力，以更快地 开发一种新药来减缓阿尔茨海默病的破坏性影响。

PROJECT SUMMARY/ABSTRACT The CDC estimates that at least 200,000 older Americans (> 65 years) will have a traumatic brain injury (TBI) each year, primarily caused by a closed head injury (CHI) from a fall. The aged brain, with Alzheimer’s disease neuropathological changes, has significant reactive microglia and astrocytes and other markers of neuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis and neuroinflammation. Alzheimer’s disease poses a significant therapeutic challenge, given that pathology can develop over decades. However, we believe that it is an obtainable therapeutic goal to prevent the worsening of neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimer’s disease . Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patient outcomes. However, no drug has earned FDA approval for specific use in mild TBI. There is also limited evidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this unique population. Broad-spectrum immunosuppressants are not advisable and, while selective biologics (such as anti-TNF) are promising, they also come with the risk of increasing infection, which is problematic in an older adult population at risk for infections. Our goal is to identify targeted immunomodulatory (not, immunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribed antibiotic, Azithromycin (AZM), as an immunomodulatory agent with neuroprotective effects in spinal cord injury. Because of its safety profile, AZM is frequently prescribed as a prophylactic treatment in several conditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of- principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the central hypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in an APP/PS1 KI mouse model of Alzheimer’s disease-related pathology in the following two specific aims (SA). SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse model following a CHI. SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimer’s disease-related neuropathology in 8-month-old APP/PS1 KI mice. This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reduce damage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatment has been established, new areas of drug development and clinical research with the potential to more quickly develop a new drug to slow the devastating effects of Alzheimer’s disease can be created.