Tau-induced astrocyte senescence in Alzheimer's disease

摘要 神经系统的健康和功能依赖于星形胶质细胞，星形胶质细胞是哺乳动物中最丰富的神经胶质细胞 大脑。星形胶质细胞是大脑结构的组成部分，对大脑功能和 通过与突触的动态相互作用实现可塑性。异常磷酸化的tau蛋白蓄积 星形胶质细胞在衰老中很常见，在阿尔茨海默病(AD)中会加剧。在AD中，过度磷酸化 神经元中的tau从微管中分离出来，形成可溶的聚集体，破坏微管的稳定。 细胞骨架。致病的可溶性tau聚集体(也称为tau寡聚体)随后被释放，并将反式- 在神经元方面，促进靶细胞中tau的聚集和微管细胞骨架的不稳定。 衰老是阿尔茨海默病最大的生物学风险；然而，将衰老与阿尔茨海默病联系起来的机制仍然难以捉摸。这个 细胞衰老的发展和衰老过程中衰老细胞的积累损害组织 功能。衰老的星形胶质细胞在AD脑内积聚。我们发现，类似于跨神经元 在繁殖过程中，可溶的致病tau聚集体被传递到星形胶质细胞，在那里它们有效地触发 微管失稳和细胞衰老。Tau转导到星形胶质细胞的功能影响 然而，它对AD的贡献仍未被发掘。我们的中心假设是：(A)tau诱导的星形胶质细胞 衰老是阿尔茨海默病神经元功能障碍和认知功能下降的关键驱动因素，以及(B) Tau或衰老星形胶质细胞将通过修复神经元来治疗AD代理模型中的AD相关功能障碍 功能。我们提出了两个具体目标。目标1将定义tau传递如何导致星形胶质细胞衰老， 并将在替代物中鉴定衰老星形胶质细胞的不同亚型及其分泌因子 阿尔茨海默病的模型；目标2将(A)建立致病tau或衰老细胞的治疗潜力 去除AD相关的神经元和认知功能障碍，(B)决定人类大脑中如何积累 星形胶质细胞tau和衰老星形胶质细胞与阿尔茨海默病Aim 1中发现的分子异常有关 进展；和(C)定义目标1中确定的不同亚型衰老星形胶质细胞的发生率 在人类公元前。这项工作将首次解决tau诱导的星形胶质细胞衰老在 AD病因学，并将显著促进对致病tau(及其触发的细胞事件)和 衰老本身可以作为治疗的靶点。通过挑选星形胶质细胞衰老作为一种新的机制 对小鼠类AD发病机制的研究，将为AD的研究开辟一条全新的途径。 因为tau免疫疗法在临床上正在推进，我们将使用的感觉剂是FDA批准的， 我们的研究结果可能具有快速转化的潜力，为治疗AD和 可能是其他痴呆症。

ABSTRACT Health and function of the nervous system relies on astrocytes, the most abundant glial cell in the mammalian brain. Astrocytes are integral components of brain architecture, and critically regulate brain function and plasticity through dynamic interactions with synapses. Accumulation of abnormally phosphorylated tau protein in astrocytes is common in aging and is exacerbated in Alzheimer's disease (AD). In AD, hyper-phosphorylated tau in neurons detaches from microtubules to form soluble aggregates, destabilizing the microtubule cytoskeleton. Pathogenic soluble tau aggregates (also called tau oligomers) are then released and transfer trans- neuronally, promoting tau aggregation and destabilization of the microtubule cytoskeleton in target cells. Aging contributes the largest biological risk for AD; yet the mechanisms that link aging to AD remain elusive. The development of cellular senescence and the accumulation of senescent cells during aging compromises tissue function. Senescent astrocytes accumulate in AD brain. We discovered that, similar to trans-neuronal propagation, soluble pathogenic tau aggregates are transmitted to astrocytes, where they potently trigger microtubule destabilization and cellular senescence. The functional impact of tau transmission to astrocytes, and its contribution to AD, however, remain unexplored. Our central hypotheses are that: (a) tau-induced astrocyte senescence is a key driver of neuronal dysfunction and cognitive decline in AD, and (b) removal of pathogenic tau or senescent astrocytes will treat AD-related dysfunction in a surrogate model of AD by restoring neuronal function. We propose two Specific Aims. Aim 1 will define how tau transmission causes astrocyte senescence, and will identify heterogeneous subtypes of senescent astrocytes and their secreted factors in a surrogate model of AD tauopathy; Aim 2 will (a) establish the therapeutic potential of pathogenic tau or senescent cell removal in AD-related neuronal and cognitive dysfunction, (b) determine, in human brains, how accumulation of astrocyte tau and of senescent astrocytes is linked to molecular abnormalities identified in Aim 1 during AD progression; and (c) define the incidence of heterogeneous subtypes of senescent astrocytes identified in Aim 1 in human AD. This work will address, for the first time, the involvement of tau-induced astrocyte senescence in AD etiology, and will markedly advance knowledge of how pathogenic tau (and the cellular events it triggers) and senescence itself can be targeted therapeutically. By singling out astrocyte senescence as a novel mechanism of AD-like pathogenesis in mice, we will open up a completely new avenue of investigation in AD. Because tau immunotherapy is being advanced in the clinic and the senolytics we will use are FDA-approved, our results could have rapid translational potential, contributing new and urgently needed tools to treat AD and potentially other dementias.