权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Brain cellular senescence as a driver of Alzheimers Disease

脑细胞衰老是阿尔茨海默病的驱动因素

基本信息

批准号：
9805419
负责人：
Veronica Galvan
金额：
$ 13.69万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805419
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Astrocytes Blood - brain barrier anatomy Brain Brain Diseases Brain Pathology Cell Aging Cell Cycle Arrest Cell division Cells Cognitive Complex Dementia Development Disease Environment Excision FDA approved FRAP1 gene Fatty acid glycerol esters GTP-Binding Proteins Genetic Goals Heterogeneity Hippocampus (Brain)Inflammation Injections Investigation J20 mouse Laboratories Lead Learning Life Link Liver Longevity Measures Mediating Memory Microglia Mitosis Mitotic Modeling Molecular Mosaicism Mus Myocardium Nervous system structure Neuroglia Neurons Outcome Pathogenesis Pathology Peripheral Permeability Pharmaceutical Preparations Phenotype Population Quercetin Reporting Research Proposals Role Severities Somatic Cell Synapses Testing Tissues Translating Work age related aging brain attenuation brain cell cell type cellular development cerebrovascular defined contribution healthspan improved inflammatory milieu innovation mouse model novel preservation prevent promoter senescence synaptic function tool vector

项目摘要

Abstract Most somatic cells accumulate molecular damage with aging, leading to the development of cellular senescence, defined as cell cycle arrest and the development of a proinflammatory `senescence-associated secretory phenotype' (SASP). Thus, with increasing age, cells with varying degrees of senescence accumulate in tissues. While some cell populations in the brain (e.g. neurons) become post-mitotic early during development, others (e.g. glia) preserve the capacity for mitosis and for bona fide senescence. Senescent astrocytes as well as neurons displaying senescent-like changes accumulate in the aging brain, and this is exacerbated in Alzheimer's disease (AD). The premise of the present studies is that cellular senescence/SASP generates a tissue environment primed to sustain diseases of aging. Inflammation is mechanistically involved in the pathogenesis of AD. While microglia and astrocytes have been implicated in AD inflammation, age-associated inflammation is due in part to increased numbers of SASP- producing senescent cells. Whether the accumulation of senescent cells in brain has a mechanistic role in AD, however, is unknown. Studies from our laboratories and others have shown that attenuation of the mammalian target of rapamycin (mTOR) potently blocks cellular senescence and SASP. Systemic mTOR attenuation also extends lifespan and healthspan in mice, and blocks AD-like progression in four different models of AD. Similarly, the elimination of senescent cells recapitulates the effects of mTOR inhibition on lifespan, improving tissue function, delaying age-related pathologies, and extending longevity in mice. Whether cell senescence/SASP contributes to the pathogenesis of AD is still unknown. Our central hypothesis is that brain cellular senescence contributes to AD-like pathogenesis in AD model mice in a manner dependent on mTOR. To test this hypothesis, we propose three Specific Aims. In Aim 1, we will ablate senescent cells systemically in a mouse model of AD using genetic tools (p16-3MR mice) and with senolytics (drugs that selectively kill senescent cells), and determine the impact on AD-relevant outcomes. In Aim 2, we will eliminate senescent astrocytes in hippocampi of AD model mice, and determine impact on synaptic, histopathological and cognitive AD-relevant outcomes. In Aim 3, we will overactivate mTOR in hippocampal astrocytes of AD mice in the presence or absence of the same senolytics as in Aim 1, and determine effects on AD-relevant outcomes. If our hypothesis is validated, this work will be significant because it will (a) define the contribution of cellular senescence/SASP to AD, and (b) define the role of mTOR in brain cellular senescence. By singling out cellular senescence as a novel mechanism of AD-like pathogenesis in mice, we will open up a completely new avenue of investigation in AD. Furthermore, because the senolytic drugs we will use are FDA- approved, our results may be rapidly translated, contributing new and urgently needed approaches to prevent or treat AD and potentially other age-related brain pathologies.

抽象的大多数体细胞随着衰老而积累分子损伤，导致细胞的发育衰老，定义为细胞周期停滞和促炎“衰老相关”的发展分泌表型（SASP）。因此，随着年龄的增长，不同程度衰老的细胞会积累在组织中。虽然大脑中的一些细胞群（例如神经元）在有丝分裂早期就变成了有丝分裂后发育，其他细胞（例如神经胶质细胞）保留有丝分裂和真正衰老的能力。衰老星形胶质细胞以及表现出衰老样变化的神经元在衰老的大脑中积累，这就是阿尔茨海默病（AD）会加剧。本研究的前提是细胞衰老/SASP 产生了一个足以维持衰老疾病的组织环境。炎症在机制上参与AD的发病机制。虽然小胶质细胞和星形胶质细胞已与 AD 炎症有关，与年龄相关的炎症部分是由于 SASP 数量增加产生衰老细胞。大脑中衰老细胞的积累是否在 AD 中具有机制作用，然而，未知。我们的实验室和其他实验室的研究表明，哺乳动物的衰减雷帕霉素靶标 (mTOR) 可有效阻止细胞衰老和 SASP。全身性 mTOR 衰减延长小鼠的寿命和健康寿命，并阻止四种不同 AD 模型的 AD 样进展。同样，衰老细胞的消除概括了 mTOR 抑制对寿命的影响，改善了组织功能，延缓与年龄相关的病理，并延长小鼠的寿命。是否细胞衰老/SASP 在 AD 发病机制中的作用尚不清楚。我们的中心假设是脑细胞衰老以某种方式促进AD模型小鼠的AD样发病机制依赖于 mTOR。为了检验这一假设，我们提出了三个具体目标。在目标 1 中，我们将消融使用遗传工具（p16-3MR 小鼠）和 senolytics 在 AD 小鼠模型中系统性地检测衰老细胞（选择性杀死衰老细胞的药物），并确定对 AD 相关结果的影响。在目标 2 中，我们将消除AD模型小鼠海马中的衰老星形胶质细胞，并确定对突触的影响，组织病理学和认知 AD 相关结果。在目标 3 中，我们将过度激活海马中的 mTOR 在存在或不存在与目标 1 中相同的 senolytics 的情况下对 AD 小鼠的星形胶质细胞进行分析，并确定对 AD 相关结果。如果我们的假设得到验证，这项工作将意义重大，因为它将 (a) 定义细胞衰老/SASP 对 AD 的贡献，以及 (b) 定义 mTOR 在脑细胞衰老中的作用。通过将细胞衰老作为小鼠 AD 样发病机制的一种新机制，我们将开辟一个新的途径。 AD 中全新的调查途径。此外，因为我们将使用的 senolytic 药物是 FDA- 如果获得批准，我们的结果可能会被迅速转化，从而提供新的、迫切需要的方法来预防或治疗 AD 和其他可能与年龄相关的脑部病变。