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: 10670998
• 负责人: Sean Curtis Bendall
• 金额: $ 36.95万
• 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/10670998
• 关键词: Address; Affect; African Green Monkey; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; American; Antibodies; Astrocytes; Automobile Driving; Axon; Biochemical; Blood Vessels; Brain; Brain imaging; Brain region; Cell Aging; Cells; Cerebellum; Cerebral cortex; Cessation of life; Clinical; Clinical Pathology; Cognitive; Communities; Complex; Data; Dementia; Dendrites; Disasters; Disease; Disease Marker; Family; Funding; Health Policy; Healthcare Systems; Heterogeneity; Hippocampus; Human; Image; Immune; Impaired cognition; Inferior; Infrastructure; Injury; Label; Lobule; Machine Learning; Maps; Measurement; Metabolic; Metals; Microglia; 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; age related neurodegeneration; 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; invention; learning strategy; loss of function; middle age; mild cognitive impairment; molecular imaging; molecular phenotype; nanometer resolution; nanoscale; neuronal cell body; neuropathology; nonhuman primate; normal aging; novel; novel imaging technique; postmitotic; 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.

项目概要/摘要 阿尔茨海默病 (AD) 是美国残疾和死亡的主要原因，也是全球主要公共卫生问题 如果我们希望避免一场带来难以言喻的痛苦的全球公共卫生灾难，时间已经不多了， 家庭的混乱，以及医疗保健系统和经济面临的严峻挑战。 仅来自创新研究 虽然衰老是 AD 的危险因素，但目前尚不清楚。 正常衰老与 AD 有何不同，以及哪些与年龄相关的因素会导致疾病。 稳态反应，旨在防止这些受损细胞在保持活力的情况下繁殖 尽管神经元具有衰老样表型，但其具有代谢活性。 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。 大脑中的神经胶质细胞和衰老样神经元随着年龄的增长而增加，被认为是导致大脑功能丧失的原因之一。 我们的应用程序名为“解耦年龄-”。 与阿尔茨海默病中的认知相关细胞衰老相比，”对目标高度敏感 RFA-AG-20-025 中概述，通过利用我们发明的创新分子成像平台 斯坦福大学；多重离子束成像（MIBI），旨在将年龄与认知衰退相关的细胞分开 MIBI 使我们能够以低纳米分辨率、高维、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（目标 2）中的相关分子（目标 1）和 AD 相关的充分表征的病例 认知障碍（目标 3） 重要的是，MIBI 允许在档案 FFPE 材料中实现所有这些， 通过创建深入的表型细胞，可以对各种现有群体进行回顾性分析。 来自我们独特的老龄化和认知群体的空间背景特征，我们将能够提供见解 通过过滤那些与衰老专门相关的因素来寻找促进认知能力下降的可改变因素。 该研究计划，临床神经病理学和认知衰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 集中在这个拟议的研究计划中，以解决空间细胞（神经/免疫、衰老）问题 非人类灵长类动物 (NHP) 和人类健康衰老和 AD 大脑模型的异质性。此外， 它将协同并利用现有基础设施中开发的专业知识来成像和组织AD 临床病理学（R01AG056287、R01AG057915、MPIs：SC Bendall、RM Angelo、TJ Montine）以及 NIA 资助的 90 多个 UCI 队列、斯坦福 ADRC 中保存的对照材料和 NHP 样本 (P50 AG047366 co-I：TJ Montine）我们将揭示区分 AD 和正常细胞的细胞衰老表型。 与年龄相关的衰老。

项目成果

Systems biology approaches to unravel lymphocyte subsets and function.

系统生物学方法揭示淋巴细胞亚群和功能。

• DOI: 10.1016/j.coi.2023.102323
• 发表时间: 2023-04-05
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Yeeun Kim;W. Greenleaf;S. Bendall
• 通讯作者: S. Bendall

Unravelling human hematopoietic progenitor cell diversity through association with intrinsic regulatory factors.

通过与内在调节因子的关联来揭示人类造血祖细胞的多样性。

• 发表时间: 2023-08-30
• 作者: Favaro, Patricia;Glass, David R;Borges, Luciene;Baskar, Reema;Reynolds, Warren;Ho, Daniel;Bruce, Trevor;Tebaykin, Dmitry;Scanlon, Vanessa M;Shestopalov, Ilya;Bendall, Sean C
• 通讯作者: Bendall, Sean C

Reproducible, high-dimensional imaging in archival human tissue by multiplexed ion beam imaging by time-of-flight (MIBI-TOF).

通过飞行时间多重离子束成像 (MIBI-TOF) 对档案人体组织进行可重复的高维成像。

• 发表时间: 2022-07
• 作者: Liu, Candace C;Bosse, Marc;Kong, Ale;Kagel, Adam;Kinders, Robert;Hewitt, Stephen M;Varma, Sushama;van de Rijn, Matt;Nowak, Stanisław H;Bendall, Sean C;Angelo, Michael
• 通讯作者: Angelo, Michael

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics.

通过单细胞蛋白质组学研究与严重登革热进展相关的人类免疫细胞反应的幅度和动力学。

• 发表时间: 2023-03-24
• 影响因子: 13.6
• 作者: Robinson, Makeda L;Glass, David R;Duran, Veronica;Agudelo Rojas, Olga Lucia;Sanz, Ana Maria;Consuegra, Monika;Sahoo, Malaya Kumar;Hartmann, Felix J;Bosse, Marc;Gelvez, Rosa Margarita;Bueno, Nathalia;Pinsky, Benjamin A;Montoya, Jose G;Maecker
• 通讯作者: Maecker

Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE.

阿尔茨海默病的单突触分析涉及病理性 tau、DJ1、CD47 和 ApoE。

• 发表时间: 2021-12-17
• 影响因子: 13.6
• 作者: Phongpreecha, Thanaphong;Gajera, Chandresh R;Liu, Candace C;Vijayaragavan, Kausalia;Chang, Alan L;Becker, Martin;Fallahzadeh, Ramin;Fernandez, Rosemary;Postupna, Nadia;Sherfield, Emily;Tebaykin, Dmitry;Latimer, Caitlin;Shively, Carol A;Regist
• 通讯作者: Regist