Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias

项目总结 到目前为止，衰老是导致各种神经退行性疾病的最重要的驱动因素和风险因素， 包括常见的阿尔茨海默病(AD)和相关的痴呆症。最近的证据来自我们的 实验室和其他机构表明，一种被称为细胞衰老的细胞命运是不同群体的有效驱动因素 从神经退化到癌症的各种与年龄相关的疾病。衰老细胞随年龄增长而增多。欠款 对于其复杂的衰老相关分泌表型(SASP)，衰老细胞可以产生深远的影响 对组织结构和功能的影响，并可能导致慢性炎症，这是许多年龄的主要贡献者- 相关的病理学。最近也有证据表明，衰老细胞可以促进衰老--尽管很少。 相关神经变性，包括阿尔茨海默病和相关痴呆。此计划的项目1项目赠款(PPG) 将深入描述人类和小鼠星形胶质细胞的衰老反应，特别是SASP， 不同应激源诱导小胶质细胞和神经元衰老。然后它将确定这些衰老的 细胞影响非衰老细胞的功能，使用同型和异型细胞培养，以及各种 从分化功能到代谢状态的终点和转录本的单细胞分析 了解衰老脑细胞群体的异质性。此外，该项目将使用三个 维度皮质类器官，包括含有野生型和野生型人类细胞的类器官 具有易患早发性阿尔茨海默病和相关痴呆的突变的基因类型。这些细胞将 来源于诱导的多能干细胞。最后，项目1将利用一种新的转基因小鼠 一种模型，允许选择性地消除衰老细胞，以确定是否衰老以及如何衰老 在活体中，细胞与年龄相关的大脑功能有因果关系。这些协作分析将补充 项目2和3提出的实验，严重依赖核心B、C和D。 将提供关于大脑中衰老细胞的前所未有的知识，关键地测试它们在推动AD中的作用 以及相关的痴呆症，并为对这些毁灭性的病理进行新的干预打开了可能性。

PROJECT SUMMARY Aging is by far the most important driver and risk factor for developing a variety of neurodegenerative diseases, including the common forms of Alzheimer’s disease (AD) and related dementias. Recent evidence from our laboratory and others indicate that a cell fate termed cellular senescence is an effective driver of a diverse group of age-related diseases ranging from neurodegeneration to cancer. Senescent cells increase with age. Owing to their complex senescence-associated secretory phenotype (SASP), senescent cells can have profound effects on tissue structure and function, and can foster chronic inflammation, a major contributor to numerous age- related pathologies. There is also recent, albeit sparse, evidence that senescent cells can contribute to age- related neurodegeneration, including AD and related dementias. Project 1 of this Program Project Grant (PPG) will characterize in depth the senescence responses, particularly the SASPs, of human and mouse astrocytes, microglia and neurons induced to senescent by different stressors. It will then determine how these senescent cells affect the function of non-senescent cells, using both homotypic and heterotypic cell cultures, and a variety of endpoints ranging from differentiated functions to metabolic state and single cell analyses of transcriptomes to understand the heterogeneity of senescent brain cell populations. In addition, the Project will use three dimensional cortical organoids, including organoids containing human cells with wild-type genotypes and those with genotypes containing mutations that predispose to early onset AD and related dementias. These cells will be derived from induced pluripotent stem cells. Finally, Project 1 will take advantage of a novel transgenic mouse model that permits the selective elimination of senescent cells in order to determine whether and how senescent cells are causally related to age-related brain function in vivo. These collaborative analyses will complement experiments proposed by Projects 2 and 3 and rely heavily on Cores B, C and D. Together, these experiments will provide unprecedented knowledge about senescent cells in the brain, critically test their role in driving AD and related dementias, and open possibilities for novel interventions into these devasting pathologies.