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

衰老和阿尔茨海默病中的星形胶质细胞和神经元脑区域和区室特异性蛋白质组动力学

• 批准号: 10630238
• 负责人: Baljit Khakh
• 金额: $ 110.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630238
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Anatomy; Area; Astrocytes; Biotinylation; Brain; Brain region; Cell membrane; Cells; Complex; Cytosol; Data; Dependovirus; Disease; Electrophysiology (science); Evaluation; Feedback; Functional disorder; Gene Expression; Hippocampus; Immunohistochemistry; Impaired cognition; Link; Location; Measures; Membrane Proteins; Methods; Molecular; Mus; Neuroanatomy; Neuroglia; Neurons; Pathogenesis; Phase; Physiology; Protein Dynamics; Proteins; Proteome; Proteomics; Reagent; Reporting; Risk; Seizures; Senile Plaques; Signal Transduction; Slice; TREM2 gene; Wild Type Mouse; Work; age related; brain cell; cell type; diagnostic strategy; experimental study; molecular pathology; mouse model; neuroinflammation; new therapeutic target; nonbinary; normal aging; novel diagnostics; pharmacologic; tau mutation; translational potential

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.

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了解，以开发新的诊断和疾病修改治疗方法。星形胶质细胞和神经元在大脑中共存，这两种主要细胞类型都被认为是导致AD的原因。AD的细胞期被认为包括不同脑细胞之间的反馈和前馈信号，作为最初出现的分子病理(异常的tau和Aβ)和随后的疾病表现之间的联系。已知的促进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，后遗症取决于环境。在过去，大多数与疾病相关的研究都是通过生理学评估、标志物评估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没有像这里建议的那样，或者按照FOA的要求，一起或使用细胞类型特定的蛋白质组学方法进行详细研究。因此，尽管取得了进展，但我们几乎没有关于星形胶质细胞和神经元蛋白质组在衰老过程中与AD相关的脑区或与特定和明确的异常相关的脑区的准确信息，例如AD的癫痫活动。我们的总体假设是，在正常衰老和AD小鼠模型中，星形胶质细胞和神经元显示出蛋白质动力学，这些变化反映了在AD发病的细胞期和AD异常癫痫活动及其相关的认知功能下降期间这些主要脑细胞之间的信号传递。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(质膜和胞浆)特异性蛋白质组学方法。目的2将测定小鼠正常衰老过程中星形胶质细胞和神经元蛋白质组的动态变化。目的3将测定AD模型小鼠异常网络活动期间的星形胶质细胞和神经元蛋白质组动力学。使用数据驱动的无偏见方法了解主要脑细胞类型(星形胶质细胞和神经元)的细胞、大脑区域和隔室特定蛋白质变化的身份和程度，对于翻译和机械工作的新机会可能是基础和催化的。