PCP4 Promotes Alzheimer’s Disease Pathogenesis by Affecting Amyloid-β Protein Precursor Processing

Article type: Research Article

Authors: Hu, Dongjie^a | Dong, Xiangjun^a | Wang, Qunxian^a | Liu, Mingjing^a | Luo, Shuyue^a | Meng, Zijun^a | Feng, Zijuan^a | Zhou, Weihui^{a; *} | Song, Weihong^{a; b; c; *}

Affiliations: [a] Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China | [b] Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and the Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China | [c] Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China

Correspondence: [*] Correspondence to: Dr. Weihong Song, MD, PhD, FCAHS, Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and the Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. E-mail: weihong@wmu.edu.cn; ORCID: https://orcid.org/0000-0001-9928-889X. and Dr. Weihui Zhou, MD, PhD, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China. E-mail: zwh@hospital.cqmu.edu.cn.

Abstract: Background:Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer’s disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. Objective:To explore the role of PCP4 in amyloid-β protein precursor (AβPP) processing in AD. Methods:In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AβPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. Results:We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AβPP. The production of amyloid-β protein (Aβ) was also promoted by PCP4. The upregulation of endogenous AβPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aβ deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. Conclusion:Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AβPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aβ pathology.

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, Down’s syndrome, Purkinje cell protein 4

DOI: 10.3233/JAD-230192

Journal: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 737-750, 2023