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使用邻近连接分析法检测、可视化和定量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.

作者信息

Romero-Fernandez Wilber, Carvajal-Tapia Cristian, Prusky Alex, Katdare Ketaki, Wang Emmeline, Shostak Alena, Ventura-Antunes Lissa, Harmsen Hannah, Lippmann Ethan, Borroto-Escuela Dasiel, MacGurn Jason, Fuxe Kjell, Schrag Matthew

机构信息

Vanderbilt University Medical Center.

Vanderbilt University.

出版信息

Res Sq. 2023 Feb 16:rs.3.rs-2570335. doi: 10.21203/rs.3.rs-2570335/v1.

DOI:10.21203/rs.3.rs-2570335/v1
PMID:36824944
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9949263/
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 proximity ligation assay (PLA) to broaden the range of molecular interactions assessable in human neuropathology. We adapted fluorescent 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 hyperphosphorylated 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

对健康和患病的人类大脑进行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，但其检测难度较大，尤其是在老年和固定的人类脑组织中。我们使用邻近连接分析（PLA）来扩大人类神经病理学中可评估的分子相互作用范围。我们对荧光PLA进行了改进，以检测患有阿尔茨海默病（AD）的人类大脑中泛素修饰的蛋白质，包括处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，微管相关蛋白tau（丝氨酸202、苏氨酸205）的过度磷酸化聚集体被泛素修饰，并且与非AD大脑相比，AD患者海马体和额叶皮质区域的磷酸化tau-泛素复合物增加。总体而言，我们改进了PLA以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/c6fd/9949263/0bc6cc9e3863/nihpp-rs2570335v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/c5099032c4b5/nihpp-rs2570335v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/b91ca9611330/nihpp-rs2570335v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/59aca3cce7c8/nihpp-rs2570335v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/bd12e7239dcb/nihpp-rs2570335v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/c1b9cdd94c89/nihpp-rs2570335v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/0bc6cc9e3863/nihpp-rs2570335v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/c5099032c4b5/nihpp-rs2570335v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/b91ca9611330/nihpp-rs2570335v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/59aca3cce7c8/nihpp-rs2570335v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/bd12e7239dcb/nihpp-rs2570335v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/c1b9cdd94c89/nihpp-rs2570335v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6fd/9949263/0bc6cc9e3863/nihpp-rs2570335v1-f0006.jpg

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本文引用的文献

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PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.PLD3 是一种神经元溶酶体磷脂酶 D，与阿尔茨海默病中的β-淀粉样斑块和认知功能有关。
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tau 接近连接分析显示，在临床前阿尔茨海默病神经原纤维缠结之前存在广泛的先前未检测到的病理。
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Development of an N-Cadherin Biofunctionalized Hydrogel to Support the Formation of Synaptically Connected Neural Networks.N-钙黏蛋白生物功能化水凝胶的构建以支持具有突触连接的神经网络形成。
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