Brain cellular senescence as a driver of Alzheimers Disease

摘要 随着年龄的增长，大多数体细胞积累分子损伤，导致细胞发育， 衰老，定义为细胞周期停滞和促炎性“衰老相关” 分泌表型”（SASP）。因此，随着年龄的增长，衰老程度不同的细胞不断积累 在组织中。虽然脑中的一些细胞群（例如神经元）在有丝分裂早期变成有丝分裂后的细胞群，但在有丝分裂后的细胞群中， 有些细胞（如神经胶质细胞）保持有丝分裂和真正衰老的能力。衰老 星形胶质细胞以及神经元显示衰老样变化积累在老化的大脑，这是 在阿尔茨海默病（AD）中恶化。目前研究的前提是， 衰老/SASP产生准备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 与AD炎症有关，年龄相关的炎症部分是由于SASP数量增加， 产生衰老细胞。脑内衰老细胞的积累是否在AD中起机制作用， 然而，这是未知的。我们实验室和其他机构的研究表明， 雷帕霉素靶点（mTOR）有效阻断细胞衰老和SASP。全身mTOR衰减还 延长小鼠的寿命和健康寿命，并在四种不同的AD模型中阻断AD样进展。 类似地，衰老细胞的消除概括了mTOR抑制对寿命的影响，改善了细胞的衰老。 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。我们的核心假设是， 脑细胞衰老在AD模型小鼠中以某种方式参与AD样发病机制 依赖于mTOR。为了验证这一假设，我们提出了三个具体目标。在目标1中，我们将 使用遗传工具（p16- 3 MR小鼠）和使用衰老抑制剂在AD小鼠模型中全身性衰老细胞 （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， 将消除AD模型小鼠大脑中衰老的星形胶质细胞，并确定对突触的影响， 组织病理学和认知AD相关结局。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Aim 1中相同的衰老清除剂的情况下，测定AD小鼠的星形胶质细胞， AD相关结局。如果我们的假设得到验证，这项工作将是重要的，因为它将（a）定义 细胞衰老/SASP对AD的贡献，和（B）定义mTOR在脑细胞衰老中的作用。 通过挑选出细胞衰老作为小鼠AD样发病机制的一种新机制，我们将开辟一个新的研究领域。 一种全新的AD研究方法此外，由于我们将使用的衰老药物是FDA- 如果获得批准，我们的结果可能会迅速转化，为预防艾滋病提供新的和迫切需要的方法。 或治疗AD和其他可能与年龄相关的脑部病变。

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.