Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer's disease models

Xin-Hao Ji; Ting-Ting Liu; Ai-Hong Wei; Hui-Ping Lei; Yue Chen; Ling-Nan Wu; Ju Liu; Ying Zhang; Fei Yan; Mei-Xiang Chen; Hai Jin; Jing-Shan Shi; Shao-Yu Zhou; Feng Jin

doi:10.3389/fnagi.2023.1218267

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer's disease models

Front Aging Neurosci. 2023 Aug 31:15:1218267. doi: 10.3389/fnagi.2023.1218267. eCollection 2023.

Authors

Xin-Hao Ji¹, Ting-Ting Liu¹, Ai-Hong Wei¹, Hui-Ping Lei¹, Yue Chen², Ling-Nan Wu¹, Ju Liu¹, Ying Zhang¹, Fei Yan¹, Mei-Xiang Chen¹, Hai Jin³, Jing-Shan Shi¹, Shao-Yu Zhou¹, Feng Jin¹

Affiliations

¹ Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
² Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
³ Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.

Abstract

Objective: To investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis.

Methods: RIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of hnRNP A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of hnRNP A1 was used to observe the effect of overexpression of hnRNP A1 on glycolysis of Aβ_25-35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay.

Results: The results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aβ_25-35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of hnRNP A1 binding to amyloid precursor protein (APP) RNA was found to increase Aβ expression, while Aβ_25-35 also down-regulated hnRNP A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

Keywords: APP; Alzheimer’s disease; HK1; glucose metabolism; hnRNP A1; neuron; p-p38 MAPK; β-amyloid.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82060727, 81660599, and 82260806) and the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province (ZK[2023]058).