AD文献阅读第2期：Neuron—神经元纤维缠结可能是特定神经元类型对应激和突触功能障碍作出反应的结果，且和细胞死亡无关！

中文摘要

神经纤维缠结（NFT）中的Tau蛋白异常聚集与阿尔茨海默病（AD）的神经变性和认知能力下降密切相关。然而，区分易聚集和抗聚集细胞状态的分子特征尚不清楚。研究人员开发了从人类AD脑中高通量分离和转录组分析具有NFT的神经元胞体的方法，量化了20种新皮质亚型对NFT形成和死亡的易感性，并鉴定了共享和细胞类型特异性特征。携带NFT的神经元共享突触传递相关基因的显著上调，包括一组63个富含突触囊泡循环的核心基因。氧化磷酸化和线粒体功能障碍是细胞高度特异性的。细胞凋亡仅适度增加，携带NFT和无NFT的神经元对死亡的敏感性高度相似。他们的分析表明，NFT代表了对压力和突触功能障碍的细胞类型特异性反应。他们为发现生物标志物和研究神经变性的tau依赖性和tau非依赖性机制提供了灵感。

英文摘要

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.

参考文献：Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease.Neuron. 2022 Sep 21;110(18):2929-2948.e8. doi: 10.1016/j.neuron.2022.06.021. Epub 2022 Jul 25.

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