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

项目摘要 到目前为止，衰老是发展各种神经退行性疾病的最重要驱动因素和风险因素， 包括阿尔茨海默病（AD）和相关痴呆的常见形式。我们最近的证据显示， 实验室和其他研究表明，称为细胞衰老的细胞命运是不同群体的有效驱动力， 从神经退化到癌症的衰老相关疾病。衰老细胞随着年龄增长而增加。由于 对于复杂的衰老相关分泌表型（SASP），衰老细胞可以对 对组织结构和功能的影响，并可促进慢性炎症，这是许多年龄- 相关的病理。最近也有证据表明，衰老细胞可以促进衰老，尽管证据很少- 相关的神经变性，包括AD和相关的痴呆。项目资助（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， 小胶质细胞和神经元在不同应激源诱导下的衰老。它将决定这些衰老的 细胞影响非衰老细胞的功能，使用同型和异型细胞培养物，以及各种 从分化功能到代谢状态的终点和转录组的单细胞分析 来了解衰老脑细胞群体的异质性。此外，该项目将使用三个 三维皮质类器官，包括含有具有野生型基因型的人细胞的类器官和那些 基因型中含有易患早发性AD和相关痴呆的突变。这些细胞将 来源于诱导多能干细胞。最后，项目1将利用一种新的转基因小鼠 一种允许选择性消除衰老细胞以确定是否以及如何衰老的模型 细胞与体内年龄相关的脑功能有因果关系。这些合作分析将补充 项目2和3提出的实验，严重依赖于核心B、C和D。总之，这些实验 将提供有关大脑衰老细胞的前所未有的知识，严格测试它们在驱动AD中的作用， 以及相关的痴呆症，并为这些毁灭性的病理学提供了新的干预手段。

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.