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.

项目总结/摘要 衰老细胞产生衰老相关分泌表型（SASP），其涉及促炎性和 促氧化因子，其可引起对邻近细胞的有害的旁分泌样作用。独立于 在一个过程中，衰老也可以从衰老的旁观者细胞传播到非衰老的旁观者细胞 这就是所谓的衰老诱导衰老（SIS）。神经元在历史上被认为是无法接受 细胞衰老然而，最近的研究提供了证据，表明神经元可能能够经历 在正常的衰老和疾病过程中的衰老。选择性杀死衰老细胞的抗衰老药物， 例如，已经显示出改善阿尔茨海默病（AD）和相关疾病的动物模型的脑功能。 痴呆症这种新方法非常重要--临床试验研究淀粉样蛋白β（Aβ）的功效 抗体导致了令人失望的失败，并且迄今为止还没有已知的疾病修饰治疗方法， 鉴定然而，对于AD和相关疾病使用senolytics有一个警告。目前还不知道是否 senolytics杀死衰老的神经胶质细胞和备用神经元，因为他们不能衰老，或者如果senolytics不仅杀死 衰老的神经胶质细胞和衰老的神经元。周围的衰老细胞通常通过 免疫细胞，包括自然杀伤（NK）细胞。由于其独特的免疫特权，大脑中的衰老细胞 可能最初能够逃避NK细胞的清除，从而使整体衰老的增加和扩散成为可能。 电池负载当免疫特权在疾病的后期受到损害时，这可能导致 包括神经元在内的衰老细胞的大规模去除。目前尚不清楚这是否有益， 对全球大脑健康有害。我们将首先评估混合原代人类神经元的衰老， 神经元星形胶质细胞的2D和3D培养物最近由我们的实验室产生，以响应A β介导的 应力然后，我们将利用一个充分表征的AD小鼠模型，即小鼠模型，确定衰老在体内的作用。 3xTg AD线。该品系与p16- 3 MR转基因小鼠模型杂交， 和衰老细胞的诱导性消融。使用这些模型将使我们能够确定：（1） 神经元、星形胶质细胞和其他CNS细胞类型经历应激介导的衰老和SASP，（2）是否 这是伴随着一个Abeta独立的SIS，（3）是否后期免疫豁免的损失，使 通过外周免疫细胞的浸润清除衰老细胞，以及（4）是否去除衰老细胞 是有益的还是有害的，以及在疾病进展的哪个阶段。