Cellular senescence, inflammation and neurotransmission in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是一个具有动态神经生物学和病理学特征的连续体 症状/标记物，因此我们需要识别新的生物标记物来优化靶向 改善病人护理的治疗方法。越来越多的证据支持与年龄相关的积累 衰老细胞、慢性炎症和谷氨酸神经传递的改变 增加AD发病风险的相互关联的机制。了解这种互动 对于确定新的治疗靶点以改善患者预后至关重要。现有数据 支持Golde和Miller提出的蛋白质病诱导AD衰老细胞假说， 可溶性和不溶性β激活先天免疫系统，触发自我加强 促炎症信号和细胞衰老的循环，最终导致 神经变性(可能通过谷氨酸神经传递的改变)和认知能力下降 在公元后。然而，Aβ42和谷氨酸神经传递在这个自我强化的循环中的作用， 以及减少细胞衰老和/或炎症是否可以防止认知能力下降， 是未知的。解决这一知识差距可能是确定潜在机制的关键 以及有能力改变功能结果的疗法。向我们的中央发表讲话 假设减轻衰老细胞的负担和改变脂肪因子和 从促炎到抗炎的细胞因子将恢复谷氨酸的神经传递，从而 延缓或防止AD相关的认知衰退，我们将针对细胞衰老(目标1)或 全身性炎症(目标2)在疾病进展过程中的两个不同时间点；1)4-5 几个月大，可溶性A-β42升高，一些斑块堆积，认知能力轻微或没有下降 2)16~17个月龄，斑块堆积明显，认知功能减退。这将允许 我们需要检查这些干预措施的长期和短期影响。这些研究将 帮助确定大脑老化和Aβ42影响发育和 AD的进展，并可能导致通过识别新的疾病阶段进行干预 特定的生物标志物和最佳治疗窗口。

Project Summary/Abstract Alzheimer’s disease (AD) lies on a continuum with dynamic neurobiological and pathological symptoms / markers, therefore we need to identify novel biomarkers to optimize targeted therapies for improved patient care. Increasing evidence support that age-related accumulation of senescent cells, chronic inflammation, and altered glutamate neurotransmission represent inter-related mechanisms that increase the risk for developing AD. Understanding this interaction is crucial to identifying novel therapeutic targets for improving patient outcome. Existing data support the proteinopathy-induced senescent cell hypothesis of AD proposed by Golde and Miller, whereby soluble and insoluble Aβ activates the innate immune system triggering a self-reinforcing cycle of pro-inflammatory signaling and cellular senescence, ultimately leading to neurodegeneration (possibly through altered glutamate neurotransmission), and cognitive decline in AD. However, the role of Aβ42 and glutamate neurotransmission in this self-reinforcing cycle, and whether decreasing cellular senescence and / or inflammation can prevent cognitive decline, is unknown. Addressing this gap in knowledge may be key to identifying underlying mechanisms and therapeutics that have the ability to alter functional outcomes. To address our central hypothesis that reducing the burden of senescent cells and shifting the profile of adipokines and cytokines from pro- to anti-inflammatory will restore glutamate neurotransmission and thereby slow or prevent AD-related cognitive decline, we will target cellular senescence (Aim 1) or systemic inflammation (Aim 2) at two distinct time points during disease progression; 1) 4-5 months of age, elevated soluble Aβ42, some plaque buildup, and little to no cognitive decline, and 2) 16-17 months of age, significant plaques accumulation and cognitive decline. This will allow us to examine both the long term and short term effects of these interventions. The studies will help determine the mechanisms by which brain aging and Aβ42 impacts the development and progression of AD and may lead to interventions through identification of novel, disease stage specific biomarkers and optimal therapeutic treatment windows.