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

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.

Automated summary

This study explores the role of Purkinje cell protein 4 (PCP4) in the progression of Alzheimer's disease (AD). PCP4 overexpression affects the processing of amyloid-beta protein precursor (AβPP) and promotes the production and deposition of amyloid-beta (Aβ). It also exacerbates learning and memory impairment in AD model mice. PCP4 may serve as a potential therapeutic target for AD by targeting Aβ pathology.