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Multilayered N-glycoproteomics reveals impaired N-glycosylation promoting Alzheimer's disease

By Pan Fang, Juan-Juan Xie, Shao-Ming Sang, Lei Zhang, Mingqi Liu, Lu-Jie Yang, Yi-Teng Xu, Guo-Quan Yan, Jun Yao, Xing Gao, Wen-Jing Qian, Zhong-Feng Wang, Yang Zhang, Pengyuan Yang, Hua-Li Shen

Posted 22 Apr 2019
bioRxiv DOI: 10.1101/615989

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that currently lacks clear pathogenesis and effective treatment. Protein glycosylation is ubiquitous in brain tissue and site-specific analysis of N-glycoproteome, which is technically challenging, can advance our understanding of the glycoproteins' role in AD. In this study, we profiled the multilayered variations in proteins, N-glycosites, N-glycans, and in particular site-specific N-glycopeptides in the APP/PS1 and wild type mouse brain through combining pGlyco 2.0 strategy with other quantitative N-glycoproteomic strategies. The comprehensive brain N-glycoproteome landscape was constructed, and rich details of the heterogeneous site-specific protein N-glycosylations were exhibited. Quantitative analyses explored generally downregulated N-glycosylation involving proteins such as glutamate receptors, as well as fucosylated and oligo-mannose type glycans in APP/PS1 mice versus wild type mice. Moreover, our preliminary functional study revealed that N-glycosylation was crucial for the membrane localization of NCAM1 and for maintaining the excitability and viability of neuron cells. Our work offered a panoramic view of the N-glycoproteomes in Alzheimer's disease and revealed that generally impaired N-glycosylation promotes Alzheimer's disease progression.

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