Astrocyte and neuron brain-region and compartment-specific proteome dynamics in aging and Alzheimer’s disease

阿尔茨海默病（AD）是一种复杂的年龄依赖性疾病。它需要多种方法在分子水平上全面理解，以开发新的诊断和疾病修饰治疗。星形胶质细胞和神经元在大脑中共存，已知这两种主要细胞类型都与阿尔茨海默病有关。AD的细胞期包括不同脑细胞之间的反馈和前馈信号，作为分子病理（异常tau和a β）的初始出现与随后的疾病表现之间的联系。已知参与这一细胞期的胶质细胞蛋白是APOE和TREM2，它们与AD风险的显著增加有关。此外，已知的星形胶质细胞机制包括反应性，这是一种复杂的非二元现象，其后遗症取决于环境。过去，大多数与疾病相关的研究都是通过生理学、标志物或基因表达评估来评估星形胶质细胞或神经元。星形胶质细胞和神经元还没有被详细地研究过，也没有按照FOA的要求，用细胞类型特异性蛋白质组学方法研究过。因此，尽管取得了进展，但我们对与阿尔茨海默病相关的大脑区域衰老过程中星形胶质细胞和神经元的蛋白质组学或与阿尔茨海默病的癫痫活动等特定和定义异常相关的大脑区域的蛋白质组学知之甚少。我们的首要假设是，星形胶质细胞和神经元在正常衰老和AD小鼠模型中表现出蛋白质动态，这些变化反映了AD发病细胞阶段和异常癫痫发作活动及其相关认知能力下降期间这些优势脑细胞之间的信号传导。目的1将描述星形胶质细胞和神经元的细胞、脑区域和隔室（质膜与细胞质溶胶）特异性蛋白质组学方法。目的2将确定小鼠正常衰老过程中星形细胞和神经元的蛋白质组动力学。目的3将测定阿尔茨海默病模型小鼠异常网络活动期间星形细胞和神经元的蛋白质组动力学。利用数据驱动的无偏方法了解主要脑细胞类型（星形胶质细胞和神经元）的细胞、脑区域和室特异性蛋白质变化的特性和程度，可能是基础和催化，为翻译和机制工作提供了新的机会。

Alzheimer’s disease (AD) is a complex age-dependent disorder. It requires multiple approaches to comprehensively understand at a molecular level in order to develop novel diagnostics and disease modifying treatments. Astrocytes and neurons coexist in the brain and both major cell types are known to contribute to AD. The cellular phase of AD is proposed to comprise feedback and feedforward signaling between diverse brain cells as a link between the initial emergence of molecular pathology (abnormal tau and Aβ) and subsequent disease manifestations. Known glial cell proteins that contribute to this cellular phase are APOE and TREM2, and are associated with significantly increased risk of AD. Moreover, known astrocyte mechanisms include reactivity, which is a complex, non-binary phenomenon with sequelae that depends on context. In the past, most disease related studies have evaluated astrocytes or neurons using assessments of physiology, markers, or with gene expression evaluations. Astrocytes and neurons have not been studied in detail together or with cell-type specific proteomic methods, as proposed here and as requested by the FOA. As a result, despite advances, we have little precise information about the proteomes of astrocytes and neurons during aging in brain areas relevant to AD or in brain regions relevant to specific and defined abnormalities such as seizure activity in AD. Our overarching hypothesis is that astrocytes and neurons display protein dynamics during normal ageing and in mouse models of AD and that these changes reflect signaling between these dominant brain cells during the cellular phase of AD pathogenesis and during aberrant seizure activity and its associated cognitive decline in AD. Aim 1 will characterize cell, brain region, and compartment (plasma membrane versus cytosol) specific proteomic methods for astrocytes and neurons. Aim 2 will determine astrocyte and neuron proteomic dynamics during normal aging in mice. Aim 3 will determine astrocyte and neuron proteomic dynamics during aberrant network activity in AD model mice. Understanding the identities and the extent of cell, brain region, and compartment-specific protein changes for the major brain cell types (astrocytes and neurons) using data-driven unbiased approaches could be foundational and catalytic with regards to new opportunities for translational and mechanistic work.