原发性年龄相关性tau蛋白病和阿尔茨海默病中海马tau蛋白病理的转录特征。
Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer's disease.
作者信息
Stein-O'Brien Genevieve L, Palaganas Ryan, Meyer Ernest M, Redding-Ochoa Javier, Pletnikova Olga, Guo Haidan, Bell William R, Troncoso Juan C, Huganir Richard L, Morris Meaghan
机构信息
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Baltimore, MD 21218, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Cell Rep. 2025 Mar 25;44(3):115422. doi: 10.1016/j.celrep.2025.115422. Epub 2025 Mar 13.
In primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated in disease overall but up-regulated in tau-pathology-positive neurons. Two transcriptional signatures were associated with intraneuronal tau, both validated in a cortical AD dataset. Genes in the up-regulated signature were enriched in calcium regulation and synaptic function. Notably, transcriptional changes associated with intraneuronal tau in PART and AD were similar, suggesting a possible mechanistic relationship. These findings highlight the power of molecular analysis stratified by pathology and provide insight into common pathways associated with tau pathology in PART and AD.
在原发性年龄相关性tau蛋白病（PART）和阿尔茨海默病（AD）中，tau蛋白聚集体具有相似的结构和解剖分布，这与其他疾病中的tau蛋白病理不同。然而，PART和AD之间的转录相似性以及tau蛋白病变神经元内的基因表达变化在很大程度上尚不清楚。使用GeoMx空间转录组学，对PART和AD中有无tau蛋白病变的海马神经元中的mRNA进行了定量分析。总体而言，疾病中突触基因下调，但在tau蛋白病变阳性神经元中上调。两种转录特征与神经元内tau蛋白相关，均在皮质AD数据集中得到验证。上调特征中的基因在钙调节和突触功能方面富集。值得注意的是，PART和AD中与神经元内tau蛋白相关的转录变化相似，提示可能存在机制上的联系。这些发现突出了按病理分层进行分子分析的作用，并为PART和AD中与tau蛋白病理相关的共同途径提供了见解。
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