Kolling Louis J, Chimenti Michael S, Marcinkiewcz Catherine A
Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA.
Iowa Institute of Human Genetics Bioinformatics Division, University of Iowa, IA City, IA, USA.
J Alzheimers Dis. 2025 Jan;103(1):133-148. doi: 10.1177/13872877241299119. Epub 2024 Nov 25.
Persons with Alzheimer's disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate.
We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology.
The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest.
We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA .
may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.
阿尔茨海默病（AD）患者会出现情绪、睡眠和觉醒方面的变化，这些变化可能先于认知能力下降的临床表现出现。这些早期症状可能由脑干中血清素能（5-HT）核团的变化驱动，特别是中缝背核（DRN）。目前尚不清楚为什么并非所有5-HT神经元都会同时出现以相同速度进展的AD病理变化。
我们试图确定与5-HT神经元对AD病理易感性或抗性相关的任何潜在遗传成分。
使用Visium空间基因表达平台来识别早期AD临床前模型——人tau蛋白过表达小鼠（htau小鼠）中DRN的转录组变化。我们进一步使用RNAscope和免疫组织化学评估来验证主要研究结果。
我们发现htau小鼠的DRN差异表达与AD相关的基因，包括那些与激酶结合、离子通道活性、配体-受体相互作用以及丝氨酸/苏氨酸激酶调节相关的基因。我们进一步发现，DRN的计算亚聚类与先前基于神经回路驱动的特征一致，从而能够对DRN内不同亚区域进行空间界定。在这些亚区域中，我们发现背外侧DRN优先受到5-HT神经元丢失和tau病理发展的影响，这与长链非编码RNA的表达增加相吻合。
可能发挥与tau磷酸化相关的调节作用，值得进一步研究以表征其相互作用。总体而言，本报告展示了大规模空间转录组学技术的强大功能，同时强调了需要进行数据验证以克服其局限性。
