Depletion of nuclear cytoophidia in Alzheimer's disease.

Q3 Medicine
Free neuropathology Pub Date : 2025-03-07 eCollection Date: 2025-01-01 DOI:10.17879/freeneuropathology-2025-6282
Alyona Ivanova, David G Munoz, John Woulfe
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引用次数: 0

Abstract

There is considerable evidence for a role for metabolic dysregulation, including disordered purine nucleotide metabolism, in the pathogenesis of Alzheimer's disease (AD). Purine nucleotide synthesis in the brain is regulated with high fidelity to co-ordinate supply with demand. The assembly of some purine biosynthetic enzymes into linear filamentous aggregates called "cytoophidia" (Gk. Cellular "snakes") represents one post-translational mechanism to regulate enzyme activity. Cytoophidia comprised of the nucleotide biosynthetic enzymes inosine monophosphate dehydrogenase (IMPDH) and phosphoribosyl pyrophosphate synthetase (PRPS) have been described in neuronal nuclei (nuclear cytoophidia; NCs). In light of the involvement of purine nucleotide dysmetabolism in AD, the rationale for this study was to determine whether there are disease-specific qualitative or quantitative alterations in PRPS cytoophidia in the AD brain. Double fluorescence immunostaining for PRPS and the neuronal marker MAP2 was performed on tissue microarrays of cores of temporal cortex extracted from post-mortem tissue blocks from a large cohort of participants with neuropathologically confirmed AD, Lewy body disease (LBD), progressive supranuclear palsy, and corticobasal degeneration, as well as age-matched cognitively unimpaired control participants. The latter group included individuals with substantial beta-amyloid deposition. NCs were significantly reduced in frequency in AD samples relative to those from controls, including those with a high beta-amyloid load, or participants with LBD or 4 repeat tauopathies. Moreover, double staining for PRPS and hyperphosphorylated tau revealed evidence for an association between NCs and neurofibrillary tangles. The results of this study contribute to our understanding of metabolic contributions to AD pathogenesis and provide a novel avenue for future studies. Moreover, because PRPS filamentation is responsive to a variety of drugs and metabolites, they may have implications for the development of biologically rational therapies.

阿尔茨海默病中嗜核细胞的减少。
有相当多的证据表明代谢失调,包括嘌呤核苷酸代谢紊乱,在阿尔茨海默病(AD)的发病机制中起作用。脑内嘌呤核苷酸的合成受到高保真度的调节,以协调供求关系。一些嘌呤生物合成酶组装成线状丝状聚集体,称为“嗜胞体”。细胞“蛇”)代表了一种调节酶活性的翻译后机制。由核苷酸生物合成酶肌苷单磷酸脱氢酶(IMPDH)和磷酸核糖基焦磷酸合成酶(PRPS)组成的嗜细胞性已经在神经元细胞核中被描述(核嗜细胞性;nc)。鉴于嘌呤核苷酸代谢异常与阿尔茨海默病有关,本研究的基本原理是确定阿尔茨海默病大脑中PRPS嗜胞质是否存在疾病特异性的定性或定量改变。研究人员对从死后组织块中提取的颞叶皮层核心组织微阵列进行了PRPS和神经元标记物MAP2的双荧光免疫染色,这些组织块来自神经病理学证实为AD、路易体病(LBD)、进行性核上性麻痹和皮质基底变性的大队列参与者,以及年龄匹配的认知功能正常的对照组参与者。后一组包括大量β -淀粉样蛋白沉积的个体。与对照组相比,AD样本中NCs的频率显著降低,包括那些β -淀粉样蛋白含量高的人,或患有LBD或4次重复tau病变的参与者。此外,PRPS和过度磷酸化的tau的双重染色显示nc和神经原纤维缠结之间存在关联的证据。本研究结果有助于我们理解代谢在AD发病机制中的作用,并为未来的研究提供了新的途径。此外,由于PRPS纤维对多种药物和代谢物有反应,它们可能对生物合理疗法的发展有影响。
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
CiteScore
2.80
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0.00%
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3 weeks
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