Selective vulnerability of cell types in brain aging and Alzheimer's disease

项目摘要 衰老和神经退化的主要标志包括认知能力下降，身体成分改变， 昼夜节律失调和神经内分泌系统的变化。下丘脑是大脑 该区域具有协调这些重要功能的多种神经元亚型。然而， 下丘脑的这种变化是正常衰老和神经退行性变中功能下降的基础， 很好理解。有趣的是，针对下丘脑的干预可以显著延长小鼠的寿命， 女性和男性的差异。此外，睡眠和体重的变化可能发生在 神经变性的发作，例如在阿尔茨海默病（AD）中。理解这一点的一个挑战是， 衰老过程是高度异质性的，这意味着不同类型的细胞衰老不同。比如说， 在大脑老化中，在个体内，免疫细胞（小胶质细胞）的年龄与神经元非常不同。此外，委员会认为， 在个体中，女性更容易患上与年龄相关的神经退行性疾病， 老年痴呆症（AD）的发病率高于男性。然而，大脑中不同细胞类型的选择性脆弱性， 衰老和AD，以及大脑衰老中女性偏见的细胞类型特异性机制在很大程度上是未知的。 在布朗大学韦伯博士的实验室里，我将在这个提议的F99阶段， 这是一项基础性工作，在这项工作中，我定义了衰老雌性小鼠中发生的细胞类型转录变化， 下丘脑我将执行机器学习分析，以识别细胞脆弱性和弹性的特征 并将这项工作扩展到神经变性模型（AD小鼠模型和人死后模型）。 组织）。了解衰老和AD的选择性脆弱性有助于制定精确的干预措施， 专门针对脆弱的神经元来减缓大脑衰老并促进健康寿命。 对于本提案的K00阶段，我将寻求了解调节 大脑老化的性别差异我之前的分析发现，Xist的表达增加， 用于在真兽目哺乳动物的雌性中沉默两个chrX中的一个，在衰老和AD脑中。由于chrX是 丰富的神经和免疫基因，以及已知的异染色质在衰老中的丢失，我假设Xist 是维持chrX沉默以保护脑老化中的神经元所必需的。我将测试这个假设， 表观遗传学上激活或沉默来源于老化成纤维细胞的诱导神经元中的Xist，以确定 对神经元老化的影响，并在体内揭示对chrX特异性扰动的细胞类型特异性响应。 这项工作将有助于理解异质性，特别是细胞类型特异性和 性别特异性的脆弱性，在正常的大脑老化和AD。此外，它将导致新的生物标志物的发现 以单细胞分辨率评估年龄和AD状态，这将有助于细胞类型的发展。 具体干预措施。为了成功地完成这些目标，我将从一个团队获得广泛的培训， 计算生物学、衰老生物学、神经退化和神经科学方面的专家。

Project Summary Major hallmarks of aging and neurodegeneration include cognitive decline, altered body composition, dysregulation of circadian rhythms, and changes in neuroendocrine systems. The hypothalamus is the brain region that harbors a diversity of neuronal subtypes that coordinate these important functions. Yet, the extent to which changes in the hypothalamus underlie functional decline in normal aging and neurodegeneration is not well understood. Intriguingly, interventions targeting the hypothalamus can significantly extend lifespan in mice, with a discrepancy in females versus males. Moreover, alterations in sleep and body weight can occur prior to the onset of neurodegeneration, for example in Alzheimer’s Disease (AD). One challenge in understanding the aging process is that it is highly heterogeneous, meaning that different cell-types age differently. For example, in brain aging, within individuals, the immune cells (microglia) age very differently from neurons. Moreover, across individuals, women are more susceptible to age-associated neurodegenerative diseases such as Alzheimer’s disease (AD) than men. However, the selective vulnerability of different cell-types in the brain in aging and AD, and the cell-type specific mechanism underlying female bias in brain aging are largely unknown. For the F99 phase of this proposal, in Dr. Webb’s laboratory at Brown University, I will build on my foundational work in which I defined the cell-type transcriptional changes that occur in the aging female mouse hypothalamus. I will perform machine learning analysis to identify signatures of cell vulnerability and resilience with age and extend this work to a model of neurodegeneration (AD mouse models and human post-mortem tissue). Understanding the selective vulnerability in aging and AD can help develop precise interventions to specifically target the vulnerable neurons to slow down brain aging and promote health span. For the K00 phase of this proposal, I will seek to understand the epigenetic mechanisms regulating sex-differences in brain aging. My previous analysis found increased expression of Xist, the master regulator for silencing one of the two chrX in females in eutherian mammals, in aging and AD brain. Given that chrX is enriched for neural and immune genes and the known loss of heterochromatin in aging, I hypothesize that Xist is required for maintaining chrX silencing to protect neurons in brain aging. I will test this hypothesis by epigenetically activating or silencing Xist in induced neurons derived from aged fibroblasts to determine the impact on neuronal aging, and in vivo to reveal the cell-type specific response to the chrX-specific perturbation. This work will contribute to the understanding of the heterogeneity, especially cell-type specific and sex-specific vulnerability, in normal brain aging and AD. Further, it will lead to the discovery of novel biomarkers to assess age and AD status at single cell resolution, which will contribute to the development of cell-type specific interventions. To successfully complete these goals, I will gain extensive training from a team of experts in computational biology, biology of aging, neurodegeneration, and neuroscience.