Tau-induced astrocyte senescence in Alzheimer's disease

阿尔茨海默病中 Tau 诱导的星形胶质细胞衰老

• 批准号: 10044019
• 负责人: Veronica Galvan
• 金额: $ 32.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2021-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044019
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Antibodies; Architecture; Area; Astrocytes; Biological; Brain; Callithrix; Cell Aging; Cell Cycle Arrest; Cell division; Cells; Clinic; Cytometry; Cytoskeleton; Data; Dementia; Dendritic Spines; Disease Progression; Etiology; Event; Excision; FDA approved; Functional disorder; Future; Gene Expression Profiling; Health; Histopathology; Human; Immunotherapy; Impaired cognition; Incidence; Investigation; Knowledge; Life; Link; Mediator of activation protein; Microtubule Stabilization; Microtubules; Mitotic; Molecular; Molecular Abnormality; Molecular Sequence Alteration; Mus; Nervous System Physiology; Neuroglia; Neuronal Dysfunction; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Proteomics; Reporting; Research; Role; Synapses; Tauopathies; Testing; Therapeutic; Time; Tissues; Toxic effect; Work; abnormally phosphorylated tau; aged; base; biochemical tools; cell injury; cellular development; density; hyperphosphorylated tau; immunocytochemistry; in vivo; innovation; live cell microscopy; mouse model; nonhuman primate; novel; preservation; senescence; targeted treatment; tau Proteins; tau aggregation; tau mutation; tool; transmission process

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.

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 个脑袋星形胶质细胞是脑结构的组成部分，并且重要地调节脑功能， 通过与突触的动态相互作用来实现可塑性。异常磷酸化tau蛋白的蓄积 在星形胶质细胞中，这种情况在衰老中很常见，并且在阿尔茨海默病（AD）中加剧。在AD中，过度磷酸化 神经元中的tau蛋白从微管上分离形成可溶性聚集体，使微管不稳定 细胞骨架然后释放致病性可溶性tau聚集体（也称为tau寡聚体）并将其反式转移到细胞中。 在神经元上，促进tau聚集和靶细胞中微管细胞骨架的不稳定。 衰老是AD的最大生物学风险;然而，将衰老与AD联系起来的机制仍然难以捉摸。的 衰老过程中细胞衰老的发展和衰老细胞的积累损害了组织 功能衰老的星形胶质细胞在AD脑中积累。我们发现，类似于跨神经元 传播，可溶性致病性tau聚集体被传递到星形胶质细胞，在那里它们有效地触发 微管不稳定和细胞衰老。tau蛋白传递对星形胶质细胞的功能影响， 然而，其对AD贡献仍未被探索。我们的中心假设是：（a）tau诱导的星形胶质细胞 衰老是AD中神经元功能障碍和认知下降的关键驱动因素，以及（B）去除致病性神经元功能障碍和认知功能下降， tau或衰老星形胶质细胞将在AD替代模型中治疗AD相关功能障碍， 功能我们提出两个具体目标。目标1将定义tau蛋白的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异质亚型及其分泌因子， 目的2将（a）建立致病性tau或衰老细胞的治疗潜力， （B）确定在人脑中， 星形胶质细胞tau蛋白和衰老星形胶质细胞与AD期间Aim 1中鉴定的分子异常有关 进展;和（c）定义目标1中鉴定的衰老星形胶质细胞异质亚型的发生率 在人类AD中。这项工作将首次解决tau蛋白诱导的星形胶质细胞衰老在脑缺血中的作用。 AD病因学，并将显着推进如何致病tau（及其触发的细胞事件）和 衰老本身可以作为治疗目标。通过挑选星形胶质细胞衰老作为一种新的机制 AD样小鼠发病机制的研究，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进步，我们将使用的senolytics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提供新的迫切需要的工具， 可能是其他痴呆症