阿尔茨海默病患者伏隔核中胆碱能靶向 tRNA 片段的性别特异性下降。
Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.
机构信息
The Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
出版信息
Alzheimers Dement. 2023 Nov;19(11):5159-5172. doi: 10.1002/alz.13095. Epub 2023 May 9.
INTRODUCTION
Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs).
METHODS
We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation.
RESULTS
NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations.
DISCUSSION
Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.
简介
与男性相比，患有阿尔茨海默病（AD）的女性的痴呆症和胆碱能神经元的丧失速度更快，但潜在的机制尚不清楚。为了寻找这两种现象的因果贡献者，我们研究了针对胆碱能转录物的转移 RNA 片段（CholinotRFs）的 tRNA 片段（tRFs）的变化。
方法
我们分析了来自伏隔核（NAc）脑区的小 RNA 测序（RNA-Seq）数据，与 AD 大脑的下丘脑或皮质组织相比，该脑区富含胆碱能神经元；并探索了经历胆碱能分化的神经元细胞系中的小 RNA 表达。
结果
源自线粒体基因组的 NAc CholinotRFs 水平降低，与它们预测的胆碱能相关 mRNA 靶标升高相关。AD 颞叶皮层的单细胞 RNA seq 显示不同细胞类型中胆碱能转录物的性别特异性水平发生改变；相反，在胆碱能分化下的人源性神经母细胞瘤细胞中呈现出性别特异性的 CholinotRF 升高。
讨论
我们的研究结果支持 CholinotRFs 对胆碱能调节的贡献，预测其参与 AD 性别特异性胆碱能丧失和痴呆症。
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