Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Department of Computer Science, Rice University, Houston, TX 77005, USA; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Neuron. 2020 Sep 9;107(5):821-835.e12. doi: 10.1016/j.neuron.2020.06.010. Epub 2020 Jun 29.
A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.
治疗阿尔茨海默病（AD）的主要障碍是我们对选择性神经元易损性的分子机制缺乏了解，这是该疾病的一个关键特征。在这里，我们提出了一个框架，将健康小鼠一生中的高质量神经元特异性分子谱与死后人类功能基因组学和定量遗传学数据整合在一起。我们证明了在 AD 中易损和抵抗神经元的分子水平上的人类-小鼠细胞分类学的保守性，确定了与 AD 神经病理学相关的特定基因和途径，并确定了一个特定的功能基因模块，该模块是选择性易损性的基础，富含与轴突重塑相关的过程，并受淀粉样蛋白积累和衰老的影响。我们已经在 http://alz.princeton.edu 上提供了所有细胞特异性图谱和功能网络。总的来说，我们的研究为理解 AD 中最易损神经元中 Aβ、衰老和神经退行性变之间的复杂相互作用提供了一个分子框架。
