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使用邻近连接分析检测、可视化和量化人类阿尔茨海默病大脑中的蛋白质复合物。

Detection, visualization and quantification of protein complexes in human Alzheimer's disease brains using proximity ligation assay.

机构信息

Department of Neurology, Vanderbilt University Medical Center, MRBIII 465 21St Avenue S, Suite 6158, Nashville, TN, 37240, USA.

Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA.

出版信息

Sci Rep. 2023 Jul 24;13(1):11948. doi: 10.1038/s41598-023-38000-4.

DOI:10.1038/s41598-023-38000-4
PMID:37488165
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10366145/
Abstract

Examination of healthy and diseased human brain is essential to translational neuroscience. Protein-protein interactions play a pivotal role in physiological and pathological processes, but their detection is difficult, especially in aged and fixed human brain tissue. We used the in-situ proximity ligation assay (PLA) to broaden the range of molecular interactions assessable in-situ in the human neuropathology. We adapted fluorescent in-situ PLA to detect ubiquitin-modified proteins in human brains with Alzheimer's disease (AD), including approaches for the management of autofluorescence and quantification using a high-content image analysis system. We confirmed that phosphorylated microtubule-associated protein tau (Serine202, Threonine205) aggregates were modified by ubiquitin and that phospho-tau-ubiquitin complexes were increased in hippocampal and frontal cortex regions in AD compared to non-AD brains. Overall, we refined PLA for use in human neuropathology, which has revealed a profound change in the distribution of ubiquitin in AD brain and its association with characteristic tau pathologies.

摘要

对健康和患病人类大脑的检查对于转化神经科学至关重要。蛋白质-蛋白质相互作用在生理和病理过程中起着关键作用，但它们的检测很困难，特别是在老年和固定的人脑组织中。我们使用原位邻近连接测定（PLA）来扩大可在原位评估人类神经病理学中分子相互作用的范围。我们采用荧光原位 PLA 来检测阿尔茨海默病（AD）患者大脑中的泛素修饰蛋白，包括用于管理自发荧光和使用高内涵图像分析系统进行定量的方法。我们证实，磷酸化微管相关蛋白 tau（丝氨酸 202、苏氨酸 205）聚集体被泛素修饰，并且与非 AD 大脑相比，AD 患者的海马和额叶皮层区域中磷酸化 tau-泛素复合物增加。总的来说，我们改进了 PLA 用于人类神经病理学，这揭示了 AD 大脑中泛素分布的深刻变化及其与特征性 tau 病理学的关联。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/59ffa73f56bf/41598_2023_38000_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/1887a65510e3/41598_2023_38000_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/5110a3fa5e99/41598_2023_38000_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/4bf85c825725/41598_2023_38000_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/e6bffbd7e508/41598_2023_38000_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/cf13c354ac0e/41598_2023_38000_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/59ffa73f56bf/41598_2023_38000_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/1887a65510e3/41598_2023_38000_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/5110a3fa5e99/41598_2023_38000_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/4bf85c825725/41598_2023_38000_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/e6bffbd7e508/41598_2023_38000_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/cf13c354ac0e/41598_2023_38000_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a6/10366145/59ffa73f56bf/41598_2023_38000_Fig6_HTML.jpg

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