Cellular senescence and Alzheimer's disease

细胞衰老和阿尔茨海默病

• 批准号: 10044328
• 负责人: Julie Kay Andersen
• 金额: $ 189.16万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044328
• 关键词: 3xTg-AD mouse; Ablation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Antibodies; Astrocytes; Automobile Driving; Brain; Cell Aging; Cell Cycle; Cells; Clinical Trials; Cognitive; Dementia; Disease; Disease Progression; Excision; Failure; Human; Immune; Impaired cognition; In Vitro; Infiltration; Inflammatory; Laboratories; Ligands; Mediating; Mitotic; Modeling; Mus; Natural Killer Cells; Neuroglia; Neurons; Pathology; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Process; Research; Role; Senile Plaques; Stress; Temporal Lobe; Transgenic Mice; Withdrawal; abeta oligomer; age related; brain health; cell type; immune clearance; improved functioning; in vivo; mouse model; neuropathology; normal aging; novel strategies; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; paracrine; prevent; response; senescence; stressor; tau Proteins; tau phosphorylation; three dimensional cell culture

PROJECT SUMMARY / ABSTRACT Senescent cells develop a senescence-associated secretory phenotype (SASP) involving pro-inflammatory and pro-oxidative factors that can elicit deleterious paracrine-like effects on neighboring cells. Independently of the original stressor, senescence can also spread from senescent to non-senescent bystander cells in a process known as senescence-induced senescence (SIS). Neurons were historically considered to be unable to undergo cellular senescence. Recent research has however provided evidence that neurons may be able to undergo senescence during normal aging and disease. Senolytic drugs, which selectively kill senescent cells, have for example been shown to improve functions in the brains of animal models of Alzheimer’s disease (AD) and related dementias. This new approach is of great importance—clinical trials investing efficacy of amyloid beta (Aβ) antibodies have led to disappointing failures and no known disease-modifying treatments have to date been identified. There is however a caveat to the use of senolytics for AD and related disorders. It is not known whether senolytics kill senescent glial cells and spare neurons because they cannot senesce, or if senolytics not only kill senescent glial cells but also senescent neurons. Senescent cells in the periphery are normally removed by immune cells including natural killer (NK) cells. Due to its unique immune privilege, senescent cells in the brain may initially be able to evade removal by NK cells, allowing for an increase and spread in the overall senescent cell load. When immune privilege becomes compromised in later stages of the disease, this could result in a large-scale removal of senescent cells including neurons. It is unclear whether this would be beneficial or detrimental to global brain health. We will initially assess neuronal senescence in mixed primary human neuronal-astrocytic 2D and 3D cultures recently generated by our laboratory in response to Abeta-mediated stress. We will then determine the role of senescence in vivo utilizing a well-characterized AD mouse model, the 3xTg AD line. This line has been crossed with a p16-3MR transgenic mouse model that allows the identification and inducible ablation of senescent cells. Use of these models will allow us to determine: (1) the ability of neurons, astrocytes, and other CNS cell types to undergo stress-mediated senescence and a SASP, (2) whether this is accompanied by an Abeta-independent SIS, (3) whether late-stage losses in immune privilege enables clearance of senescent cells via infiltration of peripheral immune cells, and (4) whether senescent cell removal is beneficial or detrimental and at what stage of disease progression.

项目摘要 /摘要 衰老细胞形成涉及促炎和的感应相关的秘密表型（SASP） 促氧化因素会引起对邻近细胞的有害旁分泌样作用。独立于 原始的压力源，在一个过程中，感应也可以从感觉旁旁观者细胞扩散 称为感应诱导的感应（SIS）。历史上认为神经元无法接受 细胞感应。但是，最近的研究提供了证据，表明神经元可能能够进行 正常衰老和疾病期间的衰老。选择性杀死感官细胞的鼻溶剂药物具有 示例显示可以改善阿尔茨海默氏病动物模型（AD）和相关动物模型的功能 痴呆症。这种新方法非常重要 - 临床试验投资淀粉样蛋白β（Aβ）的效率 抗体导致令人失望的失败，并且迄今为止尚无已知的疾病改良治疗 确定。但是，将Senolottics用于AD和相关疾病有一个警告。不知道是否 塞溶剂剂杀死感觉神经胶质细胞和备用神经元，因为它们无法感知，或者塞溶剂不仅杀死 衰老的神经胶质细胞，但也有感觉神经元。通常通过 免疫细胞包括天然杀手（NK）细胞。由于其独特的免疫特权，大脑中的感觉细胞 最初可能能够逃避NK细胞的去除，从而增加并在整体感觉中扩散 电池负载。当免疫特权在疾病的后期被损害时，这可能导致 大规模去除感官细胞，包括神经元。目前尚不清楚这是有益的还是 对全球大脑健康有害。我们最初将评估混合原代人的神经元感应 我们的实验室最近生成的ABETA介导的神经元 - 胃细胞2D和3D培养物 压力。然后，我们将使用特征良好的AD小鼠模型（即 3XTG广告线。该线已与P16-3MR转基因小鼠模型交叉，该模型允许识别 和诱导的感觉细胞的消融。这些模型的使用将使我们能够确定：（1） 神经元，星形胶质细胞和其他中枢神经系统细胞类型会经历应力介导的感应和SASP，（2）是否是否 这是由独立于Abeta的SI实现 通过外周种免疫细胞浸润的感觉细胞清除，（4）是否去除感觉细胞 是有益的或有害的，并且在疾病进展的哪个阶段。