PCP4 Promotes Alzheimer's Disease Pathogenesis by Affecting Amyloid-beta Protein Precursor Processing

作者全名："Hu, Dongjie; Dong, Xiangjun; Wang, Qunxian; Liu, Mingjing; Luo, Shuyue; Meng, Zijun; Feng, Zijuan; Zhou, Weihui; Song, Weihong"

作者地址："[Hu, Dongjie; Dong, Xiangjun; Wang, Qunxian; Liu, Mingjing; Luo, Shuyue; Meng, Zijun; Feng, Zijuan; Zhou, Weihui; Song, Weihong] Chongqing Med Univ, Chongqing Key Lab Translat Med Res Cognit Dev & L, Minist Educ,China Int Sci & Technol Cooperat Base, Key Lab Child Dev & Disorders,Natl Clin Res Ctr C, Chongqing, Peoples R China; [Song, Weihong] Wenzhou Med Univ, Inst Aging, Zhejiang Prov Clin Res Ctr Mental Disorders, Key Lab Alzheimers Dis Zhejiang Prov,Sch Mental H, Wenzhou, Zhejiang, Peoples R China; [Song, Weihong] Wenzhou Med Univ, Affiliated Wenzhou Kangning Hosp, Wenzhou, Zhejiang, Peoples R China; [Song, Weihong] Zhejiang Lab Regenerat Med Vis & Brain Hlth, Oujiang Lab, Wenzhou, Zhejiang, Peoples R China"

通信作者："Song, WH (通讯作者)，Wenzhou Med Univ, Inst Aging, Key Lab Alzheimers Dis Zhejiang Prov, Zhejiang Prov Clin Res Ctr Mental Disorders,Sch M, Wenzhou 325035, Zhejiang, Peoples R China.; Song, WH (通讯作者)，Wenzhou Med Univ, Affiliated Wenzhou Kangning Hosp, Wenzhou 325035, Zhejiang, Peoples R China.; Zhou, WH (通讯作者)，Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Translat Med Res Cognit Dev & L, Minist Educ, Key Lab Child Dev & Disorders, Chongqing, Peoples R China."

来源：JOURNAL OF ALZHEIMERS DISEASE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001035839200028

JCR分区：Q2

影响因子：3.4

年份：2023

卷号：94

期号：2

开始页：737

结束页：750

文献类型：Article

关键词：Alzheimer's disease; amyloid-beta; amyloid-beta protein precursor; Down's syndrome; Purkinje cell protein 4

摘要："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-beta protein precursor (A beta PP) 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 A beta PP 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 A beta PP. The production of amyloid-beta protein (A beta) was also promoted by PCP4. The upregulation of endogenous A beta PP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased A beta 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 A beta PP processing and suggests PCP4 as a novel therapeutic target for AD by targeting A beta pathology."

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