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

阿尔茨海默病中年龄与认知相关的细胞衰老的解耦

• 批准号: 10454751
• 负责人: Sean Curtis Bendall
• 金额: $ 37.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454751
• 关键词: Address; Affect; African Green Monkey; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; American; Antibodies; Archives; Astrocytes; Automobile Driving; Axon; Biochemical; Blood Vessels; Brain; Brain Diseases; Brain imaging; Brain region; Cell Aging; Cells; Cerebellum; Cerebrum; Cessation of life; Clinical; Clinical Pathology; Cognitive; Communities; Complex; Data; Dementia; Dendrites; Disasters; Disease; Disease Marker; Family; Funding; Gold; Health Policy; Healthcare Systems; Heterogeneity; Hippocampus (Brain); Human; Image; Immune; Impaired cognition; Inferior; Infrastructure; Injury; Label; Lobule; Machine Learning; Maps; Measurement; Metabolic; Metals; Microglia; Mitotic; Modeling; Molecular and Cellular Biology; Multiplexed Ion Beam Imaging; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Oligodendroglia; Parietal; Pathology; Pattern; Phenotype; Policy Maker; Population; Predisposition; Process; Proteins; Proteomics; Public Health; Research; Research Personnel; Resistance; Risk Factors; Running; Sampling; Senile Plaques; Severities; Specimen; Synapses; Technology; Time; Tissues; Tonsil; Validation; abeta accumulation; age related; aged; aging brain; area striata; brain tissue; cell injury; cohort; collaborative approach; deep learning; disability; entorhinal cortex; healthy aging; high dimensionality; human model; imaging platform; innovation; insight; learning strategy; loss of function; middle age; mild cognitive impairment; mind control; molecular imaging; molecular phenotype; nanometer resolution; nanoscale; neuronal cell body; neuropathology; nonhuman primate; normal aging; novel; novel imaging technique; predictive signature; prevent; programs; release factor; response; senescence; shared database; stressor; tau Proteins; therapeutic target; vervet

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.

项目摘要/摘要 阿尔茨海默病(AD)是美国导致残疾和死亡的主要原因，也是全球主要的公共卫生问题 有问题。如果我们希望避免一场痛苦不堪的全球公共卫生灾难，时间不多了， 家庭受到破坏，卫生保健系统和经济面临严峻挑战。有效的解决方案将 只能来自创新研究。虽然衰老是发展为阿尔茨海默病的最大风险因素，但尚不清楚 正常衰老在多大程度上有别于阿尔茨海默病，以及哪些年龄相关因素导致了疾病。衰老是一种 动态平衡反应，其目的是在这些受损细胞仍然存活的同时阻止它们的繁殖 新陈代谢活跃。已经在神经元中描述了衰老的表型，尽管神经元 有丝分裂后细胞和这些细胞可能会释放引发周围神经胶质细胞衰老的因子。衰老 随着年龄的增长，大脑中的胶质细胞和衰老的类神经元增加，被认为是导致大脑中 与衰老和老年性疾病相关的功能，如阿尔茨海默病。我们的申请书名为《脱钩时代-- 与阿尔茨海默病中认知相关的细胞衰老相比，《阿尔茨海默病与认知相关的细胞衰老》对目标反应强烈 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)，以将年龄与认知衰退相关的细胞分离 衰老。MIBI使我们能够以低纳米分辨率、高维度、蛋白质水平进行量化 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- 健康衰老模型中的相关分子(目标1)(目标2)和与AD相关的典型病例 认知障碍(目标3)。重要的是，MIBI允许所有这些在存档的FFPE材料中完成， 因此，可以对各种现有队列进行回溯性分析。通过创造深入的、表型的细胞 来自我们独特的老龄化和认知队列的空间背景签名，我们将能够提供洞察力 对于促进认知衰退的可修改因素，只过滤那些与衰老特别相关的因素。在……里面 这项研究计划，在临床神经病理学和认知功能减退方面的合作专业知识，技术 成像、生化/分子和细胞生物学以及机器学习分析方面的进展 汇聚在这一拟议的研究计划中，以解决空间细胞(神经/免疫、衰老) 非人灵长类动物(NHP)和健康衰老和AD大脑的人类模型的异质性。此外， 它将协同并利用现有基础设施中开发的专业知识来形象和组织广告 临床病理(R01AG056287，R01AG057915，MPIS：SC Bendall，RM Angelo，TJ Montle)以及 NIA资助的90多个UCI队列，斯坦福ADRC中存放的对照材料，以及NHP样本(P50 AG047366 co-I：TJ Montle)。我们将揭示区分AD和正常的细胞衰老表型 与年龄相关的衰老。