唐氏综合征额叶皮层第 III 层和第 V 层锥体神经元在老年个体中表现出薄层特异性变性。

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg
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引用次数: 0

摘要

在唐氏综合征(DS)和阿尔茨海默病(AD)中,神经元群都会出现选择性易损性,导致锥体神经元(PNs)不成比例地退化,从而影响记忆和执行功能。阐明这些神经元群选择性易损性的细胞机制将为了解 DS 和 AD 的疾病进展提供关键信息。研究人员对死后人类 DS 和年龄与性别匹配的对照组(CTR)大脑中对执行功能至关重要的神经元、前额叶皮层布罗德曼第 9 区(BA9)第 III 层(L3)和第 V 层(L5)兴奋性 PNs 进行了单群 RNA 序列分析。对来自各层神经元的差异表达基因(DEGs)进行了数据挖掘,并对各层神经元之间的差异表达基因进行了识别和研究。与CTR受试者相比,DS患者L3 PNs的生物信息学调查显示,L5 PNs的独特/差异表达DEGs(uDEGs)比L3 PNs的多,这表明基因失调显示了空间和皮层板层投射神经元依赖性失调。DS的人类21号染色体三倍体(HSA21)组成了一个DEGs子集,该子集仅在L3或L5神经元中失调,这表明HSA21的表达具有部分细胞特异性。这些 HSA21 uDEGs 中的非编码 RNA 数量过多,这表明特定的薄层基因调控失调。L3 uDEGs总体上显示了更多的细胞通路和过程失调,其中许多与早期AD发病机制有关,而L5则显示了提示AD病理的过程。这些研究结果表明,三体综合征会对老年 DS 患者 L3 和 L5 BA9 投射神经元中的 uDEGs 亚群产生不同程度的影响,这可能会为 DS 和 AD 的电路特异性发病机制提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals.

Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD.

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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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