Cellular senescence, inflammation and neurotransmission in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一个动态的神经生物学和病理学的连续体， 因此，我们需要识别新的生物标志物，以优化靶向 改善患者护理的治疗方法。越来越多的证据表明， 衰老细胞，慢性炎症和改变谷氨酸神经传递代表 增加发展AD风险的相互关联的机制。理解这种互动 是确定新的治疗目标，以改善患者的结果至关重要。现有数据 支持Golde和米勒提出的AD的蛋白病诱导的衰老细胞假说， 可溶性和不溶性Aβ激活先天免疫系统， 促炎信号传导和细胞衰老的循环，最终导致 神经变性（可能通过改变谷氨酸神经传递）和认知能力下降 在AD中。然而，Aβ42和谷氨酸神经传递在这种自我强化循环中的作用， 以及减少细胞衰老和/或炎症是否可以预防认知能力下降， 不明解决这一知识差距可能是确定潜在机制的关键 以及能够改变功能结果的治疗剂。向我们的中央 假设减少衰老细胞的负担和改变脂肪因子的分布， 从促炎到抗炎的细胞因子将恢复谷氨酸神经传递， 减缓或预防AD相关的认知衰退，我们将针对细胞衰老（目标1）或 在疾病进展期间的两个不同时间点的全身性炎症（目标2）; 1）4-5 月龄，可溶性Aβ42升高，一些斑块积聚，很少或没有认知能力下降， 2)16-17个月大，斑块明显堆积，认知能力下降。这将允许 我们需要研究这些干预措施的长期和短期影响。这些研究将 有助于确定大脑衰老和Aβ42影响发育的机制， AD的进展，并可能导致通过识别新的疾病阶段进行干预 特异性生物标志物和最佳治疗治疗窗。

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.