Spliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer's disease.

IF 6.2 2区 医学 Q1 CLINICAL NEUROLOGY
Brain Pathology Pub Date : 2025-03-23 DOI:10.1111/bpa.70004
Sylvia E Perez, Muhammad Nadeem, Bin He, Jennifer C Miguel, David G Moreno, Marta Moreno-Rodriguez, Michael Malek-Ahmadi, Chadwick M Hales, Elliott J Mufson
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引用次数: 0

Abstract

Default mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer's disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V-VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a significant increase in pS5-RNA pol II levels in FC NCI, U1-70K in PreC MCI and mAD, and hnRNPA2B1 and SRSF2 levels in PCC mAD. 1N3Rtau levels were significantly increased in FC, decreased in PreC in mAD, and unchanged in PCC, whereas 1N4Rtau increased in mAD across the hubs. SRSF2, U1-70K, U1A, and hnRNPA2B1 nuclear optical density (OD), size, and number were unchanged across groups in FC and PCC, while PreC OD hnRNPA2B1 was significantly greater in mAD. Mislocalized U1A and U1-70K tangle-like structures were found in a few PCC cases and colocalized with AT8-bearing neurofibrillary tangles (NFTs). FC pS5-RNA pol II, PreC U1-70K, Pre pS5,2-RNA pol II, and PCC hnRNPA2B1 and SRSF2 protein levels were associated with cognitive decline but not neuropathology across clinical groups. By contrast, splicing protein nuclear OD measures, size, counts, and mislocalized U1-70K and U1A NFT-like structures were not correlated with NFT or plaque density, cognitive domains, and neuropathological criteria in DMN hubs. Findings suggest that RNA splicing protein alterations and U1 mislocalization contribute differentially to DMN pathogenesis and cognitive deterioration in AD.

在阿尔茨海默病的进展过程中,剪接体蛋白改变区分了默认模式连接组的枢纽。
默认模式网络(DMN)由额叶(FC)、楔前叶(PreC)和后扣带(PCC)皮层组成,在阿尔茨海默病(AD)中表现出淀粉样蛋白和tau蛋白病理。PreC中心似乎对AD病理最具弹性,这表明DMN内部存在不同的脆弱性。然而,这种差异病理生物学背后的机制仍然不清楚。在这里,我们研究了RNA聚合酶II (RNA pol II)和剪接蛋白U1-70K、U1A、SRSF2和hnRNPA2B1的变化,磷酸化了FC、PreC和PCC中含有神经元和III层和V-VI层淀粉样斑块的AT8 tau、3R和4Rtau亚型,这些亚型来自临床前诊断为无认知障碍(NCI)、轻度认知障碍(MCI)和轻度/中度mAD的个体。我们发现FC NCI中pS5-RNA pol II水平显著升高,PreC MCI和mAD中U1-70K水平显著升高,PCC mAD中hnRNPA2B1和SRSF2水平显著升高。1N3Rtau水平在FC中显著升高,在mAD的PreC中显著降低,在PCC中保持不变,而1N4Rtau水平在所有枢纽中均升高。SRSF2、U1-70K、U1A和hnRNPA2B1核光密度(OD)、大小和数量在FC和PCC各组间没有变化,而PreC OD hnRNPA2B1在mAD组中显著增加。在少数PCC病例中发现错误定位的U1A和U1-70K缠结样结构,并与含at8的神经原纤维缠结(nft)共定位。FC pS5- rna pol II、PreC U1-70K、Pre pS5、2-RNA pol II和PCC hnRNPA2B1和SRSF2蛋白水平与认知能力下降有关,但与神经病理学无关。相比之下,剪接蛋白核OD测量、大小、计数和错误定位的U1-70K和U1A NFT样结构与DMN中心的NFT或斑块密度、认知域和神经病理标准无关。研究结果表明,RNA剪接蛋白改变和U1错定位在AD患者DMN发病和认知功能恶化中起着不同的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Brain Pathology
Brain Pathology 医学-病理学
CiteScore
13.20
自引率
3.10%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.
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