Uncoupling Age- Versus Cognitive-Related Cellular Senescence in Alzheimer's Disease

项目总结/摘要 阿尔茨海默病（AD）是美国残疾和死亡的主要原因，也是全球主要的公共卫生问题。 问题.如果我们希望避免一场带来无尽痛苦的全球公共卫生灾难， 家庭破裂，卫生保健系统和经济面临严峻挑战。真正的解决方案将 只来自创新研究。虽然衰老是发展AD的最大风险因素，但目前尚不清楚 正常衰老与AD的区别程度以及哪些年龄相关因素导致疾病。衰老是一种 稳态反应，其目的是防止这些受损细胞的繁殖，同时保持活力 并且新陈代谢活跃衰老样表型已经在神经元中被描述，尽管神经元是 有丝分裂后的细胞，这些细胞可以释放因子，触发周围神经胶质细胞的衰老。衰老 神经胶质和衰老样神经元在大脑中随着年龄的增长而增加，并被认为有助于丧失神经元。 与衰老和年龄相关疾病如AD相关的功能。我们的申请，题为“脱钩时代- 与阿尔茨海默病中认知相关的细胞衰老”，是高度响应的目标， 在RFA-AG-20-025中概述，通过利用我们在 斯坦福大学;多路离子束成像（MIBI），以分离年龄-认知衰退相关的细胞 衰老MIBI使我们能够以低纳米分辨率、高维、蛋白质水平进行定量 表达模式，单细胞（神经/免疫）相互作用，以及衰老和AD的空间定位。 健康老龄化模型（目标2）中的相关分子（目标1）和AD相关的良好表征病例 认知障碍（目标3）。重要的是，MIBI允许所有这些都在档案FFPE材料中完成， 从而允许对各种现有群组进行回顾性分析。通过创造深入的，表型细胞 从我们独特的老龄化和认知群体的空间背景签名，我们将能够提供洞察力， 通过过滤那些与衰老有关的因素来寻找促进认知能力下降的可改变因素。在 这项研究计划，在临床神经病理学和认知能力下降，技术 成像、生物化学/分子和细胞生物学以及机器学习分析的进步 汇聚在这个拟议的研究计划，以解决空间细胞（神经/免疫，衰老） 在非人灵长类动物（NHP）和健康老龄化和AD脑人类模型中的异质性。此外，委员会认为， 它将与现有基础设施中开发专门知识协同作用，并利用这些专门知识来建立和组织反倾销 临床病理学（R 01 AG 056287，R 01 AG 057915，MPI：SC Bendall，RM Angelo，TJ Montine）以及 NIA资助的90+ UCI队列、存放在斯坦福大学ADRC的对照材料和NHP标本（P50 AG 047366共-I：TJ Montine）。我们将揭示区分AD和正常AD的细胞衰老表型， 与年龄相关的衰老

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a leading cause of disability and death in the US and a major global public health problem. Time is running short if we wish to avert a global public health disaster with untold suffering, disruption of families, and severe challenges to health care systems and economies. Effectual solutions will come only from innovative research. While aging is the biggest risk factor for developing AD, it is unclear to what extent normal aging is distinct from AD and which age-related factors drive disease. Senescence is a homeostatic response, which aims to prevent the propagation of these damaged cells while they remain viable and metabolically active. Senescent-like phenotypes have been described in neurons despite neurons being post-mitotic cells and these cells may release factors that trigger senescence in surrounding glia. Senescent glia and senescent-like neurons increase in the brain with age and are thought to contribute to the loss of function associated with aging and age-related diseases like AD. Our application, entitled “Uncoupling Age- Versus Cognitive-Related Cellular Senescence in Alzheimer's Disease,” is highly responsive to the objectives outlined in the RFA-AG-20-025, by leveraging an innovative molecular imaging platform we invented at Stanford; multiplexed ion beam imaging (MIBI), in order to uncouple age- from cognitive decline-related cellular senescence. MIBI enables us to quantify, with low nanometer resolution, high-dimensional, protein-level expression patterns, single-cell (neuro/immune) interactions, and spatial localization of senescence- and AD- relevant molecules (Aim 1) in a model of healthy aging (Aim 2) and well-characterized cases of AD related cognitive impairment (Aim 3). Importantly, MIBI allows all of this to be accomplished in archival FFPE material, thus allowing retrospective analysis on a variety of existing cohorts. By creating in-depth, phenotypic cellular signatures with spatial context from our unique aging and cognitive cohorts, we will be able to provide insight for modifiable factors promoting cognitive decline by filtering those specifically associated with aging alone. In this research program, collaborative expertise in clinical neuropathology and cognitive decline, technological advancements in imaging, biochemical/molecular and cellular biology, and machine learning analytics converge in this proposed research program to address the spatio-cellular (neuro/immune, senescent) heterogeneity in non-human primate (NHP) and human models of healthy aging and AD brains. Furthermore, it will be synergistic to, and draw on expertise developed in existing infrastructure to image and organize AD clinical pathology (R01AG056287, R01AG057915, MPIs: SC Bendall, RM Angelo, TJ Montine) as well as the NIA-funded 90+ UCI cohort, control material housed in the Stanford ADRC, and NHP specimens (P50 AG047366 co-I: TJ Montine). We will reveal cellular senescent phenotypes that differentiate AD from normal age-associated senescence.