Comparative interactome mapping of Tau-protein in classical and rapidly progressive Alzheimer's disease identifies subtype-specific pathways.

IF 4 2区医学 Q1 CLINICAL NEUROLOGY Neuropathology and Applied Neurobiology Pub Date : 2024-02-01 DOI:10.1111/nan.12964

Abrar Younas, Neelam Younas, Muhammad Javed Iqbal, Isidre Ferrer, Inga Zerr

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Abstract

Aims: Tau is a key player in Alzheimer's disease (AD) and other Tauopathies. Tau pathology in the brain directly correlates with neurodegeneration in AD. The recent identification of a rapid variant of AD demands an urgent need to uncover underlying mechanisms leading to differential progression in AD. Accordingly, we aimed to dissect the underlying differential mechanisms of toxicity associated with the Tau protein in AD subtypes and to find out subtype-dependent biomarkers and therapeutic targets.

Methods: To identify and characterise subtype-specific Tau-associated mechanisms of pathology, we performed comparative interactome mapping of Tau protein in classical AD (cAD) and rapidly progressive AD (rpAD) cases using co-immunoprecipitation coupled with quantitative mass spectrometry. The mass spectrometry data were extensively analysed using several bioinformatics approaches.

Results: The comparative interactome mapping of Tau protein revealed distinct and unique interactors (DPYSL4, ARHGEF2, TUBA4A and UQCRC2) in subtypes of AD. Interestingly, an analysis of the Tau-interacting proteins indicated enrichment of mitochondrial organisation processes, including negative regulation of mitochondrion organisation, mitochondrial outer membrane permeabilisation involved in programmed cell death, regulation of autophagy of mitochondrion and necroptotic processes, specifically in the rpAD interactome. While, in cAD, the top enriched processes were related to oxidation-reduction process, transport and monocarboxylic acid metabolism.

Conclusions: Overall, our results provide a comprehensive map of Tau-interacting protein networks in a subtype-dependent manner and shed light on differential functions/pathways in AD subtypes. This comprehensive map of the Tau-interactome has provided subsets of disease-related proteins that can serve as novel biomarkers/biomarker panels and new drug targets.

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典型阿尔茨海默病和快速进展性阿尔茨海默病中 Tau 蛋白的相互作用组比较图谱确定了亚型特异性通路。

目的：Tau 是阿尔茨海默病（AD）和其他 Tau 病的关键因素。大脑中 Tau 的病理变化与阿尔茨海默病的神经变性直接相关。最近发现了一种快速变异的阿尔茨海默病，这就迫切需要揭示导致阿尔茨海默病不同进展的潜在机制。因此，我们旨在剖析AD亚型中与Tau蛋白相关的毒性的潜在差异机制，并找出亚型依赖性生物标志物和治疗靶点：为了确定亚型特异性Tau相关病理机制并描述其特征，我们使用共免疫沉淀结合定量质谱法对经典AD（cAD）和快速进展AD（rpAD）病例中的Tau蛋白进行了交互组比较图谱绘制。使用多种生物信息学方法对质谱数据进行了广泛分析：结果：Tau蛋白的比较相互作用组图谱揭示了AD亚型中独特的相互作用因子（DPYSL4、ARHGEF2、TUBA4A和UQCRC2）。有趣的是，对 Tau 相互作用蛋白的分析表明，线粒体组织过程（包括线粒体组织的负调控）、线粒体外膜通透性（涉及程序性细胞死亡）、线粒体自噬调控和坏死过程（特别是在 rpAD 相互作用组中）得到了丰富。而在 cAD 中，富集程度最高的过程与氧化还原过程、运输和单羧酸代谢有关：总之，我们的研究结果以亚型依赖的方式提供了一个全面的Tau相互作用蛋白网络图，并揭示了AD亚型中的不同功能/途径。这一全面的Tau-相互作用组图谱提供了与疾病相关的蛋白质子集，可作为新型生物标记物/生物标记物面板和新的药物靶点。

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来源期刊

Neuropathology and Applied Neurobiology 医学-病理学

CiteScore

8.20

自引率

2.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Neuropathology and Applied Neurobiology is an international journal for the publication of original papers, both clinical and experimental, on problems and pathological processes in neuropathology and muscle disease. Established in 1974, this reputable and well respected journal is an international journal sponsored by the British Neuropathological Society, one of the world leading societies for Neuropathology, pioneering research and scientific endeavour with a global membership base. Additionally members of the British Neuropathological Society get 50% off the cost of print colour on acceptance of their article.