Age-Associated UBE2O Reduction Promotes Neuronal Death in Alzheimer’s Disease

Article type: Research Article

Authors: Cheng, Jing^{a; b} | Zheng, Huancheng^{a; b} | Liu, Chenyu^c | Jin, Jiabin^d | Xing, Zhenkai^{b; *} | Wu, Yili^{d; e; *}

Affiliations: [a] Cheeloo College of Medicine, Shandong University, Jinan, China | [b] Shandong Key Laboratory of Behavioral Medicine, School of Mental Health, Jining Medical University, Jining, China | [c] Zhejiang Provincial Clinical Research Center for Mental Disorders, Alberta Institute, School of Mental Health and The Affiliated Kangning Hospital, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China | [d] Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China | [e] Shandong Collaborative Innovation Center for Diagnosis, Treatment & Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China

Correspondence: [*] Correspondence to: Dr. Yili Wu, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China. E-mail: wuyili@wmu.edu.cn; Dr. Zhenkai Xing, Shandong Key Laboratory of Behavioral Medicine, School of Mental Health, Jining Medical University, Jining 272013, China. E-mail: xingzk@mail.jnmc.edu.cn.

Abstract: Background:Alzheimer’s disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly. Ubiquitin proteasome system (UPS) is critical for protein homeostasis, while the functional decline of UPS with age contributes to the pathogenesis of AD. Ubiquitin-conjugating enzyme E2O (UBE2O), an E2-E3 hybrid enzyme, is a major component of UPS. However, its role in AD pathogenesis has not been fully defined. Objective:We aimed to identify the age-associated expression of UBE2O and its role AD pathogenesis. Methods:Western blot analysis were used to assess expression of UBE2O in organs/tissues and cell lines. Immunofluorescence staining was performed to examine the cellular distribution of UBE2O. Neuronal death was determined by the activity of lactate dehydrogenase. Results:UBE2O is highly expressed in the cortex and hippocampus. It is predominantly expressed in neurons but not in glial cells. The peak expression of UBE2O is at postnatal day 17 and 14 in the cortex and hippocampus, respectively. Moreover its expression is gradually reduced with age. Importantly, UBE2O is significantly reduced in both cortex and hippocampus of AD mice. Consistently, overexpression of amyloid-β protein precursor (AβPP) with a pathogenic mutation (AβPPswe) for AD reduces the expression of UBE2O and promotes neuronal death, while increased expression of UBE2O rescues AβPPswe-induced neuronal death. Conclusion:Our study indicates that age-associated reduction of UBE2O may facilitates neuronal death in AD, while increasing UBE2O expression or activity may be a potential approach for AD treatment by inhibiting neuronal death.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, neuronal death, UBE2O, ubiquitin proteasome system

DOI: 10.3233/JAD-221143

Journal: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1083-1093, 2023