Downregulation of PIK3CB Involved in Alzheimer's Disease via Apoptosis, Axon Guidance, and FoxO Signaling Pathway.

Zhike Zhou,Kexin Kang,Shanshan Zhong,Ying Xu,Chuansheng Zhao,Jun Bai,Xiaoqian Zhang,Rongwei Zhang,Mei Zhao,Fabiana Morroni

doi:10.1155/2022/1260161

Abstract

Objective To investigate the molecular function of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) underlying Alzheimer's disease (AD). Methods RNA sequencing data were used to filtrate differentially expressed genes (DEGs) in AD/nondementia control and PIK3CB-low/high groups. An unbiased coexpression network was established to evaluate module-trait relationships by using weight gene correlation network analysis (WGCNA). Global regulatory network was constructed to predict the protein-protein interaction. Further cross-talking pathways of PIK3CB were identified by functional enrichment analysis. Results The mean expression of PIK3CB in AD patients was significantly lower than those in nondementia controls. We identified 2,385 DEGs from 16,790 background genes in AD/control and PIK3CB-low/high groups. Five coexpression modules were established using WGCNA, which participated in apoptosis, axon guidance, long-term potentiation (LTP), regulation of actin cytoskeleton, synaptic vesicle cycle, FoxO, mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) signaling pathways. DEGs with strong relation to AD and low PIK3CB expression were extracted to construct a global regulatory network, in which cross-talking pathways of PIK3CB were identified, such as apoptosis, axon guidance, and FoxO signaling pathway. The occurrence of AD could be accurately predicted by low PIK3CB based on the area under the curve of 71.7%. Conclusions These findings highlight downregulated PIK3CB as a potential causative factor of AD, possibly mediated via apoptosis, axon guidance, and FoxO signaling pathway.

Highlights

Alzheimer’s disease (AD), referring to an irreversible neurodegenerative disorder, is manifested in cognitive decline, along with behavioral and psychiatric abnormalities of varying extent [1, 2]
Imbalance of these two pathways leads to Aβ accumulation, which further elicits early synaptic alterations and synaptic loss, a process thought to be regulated by phosphoinositide 3 kinase (PI3K) [11, 12]
The cellular processes of each module were further enriched by functional enrichment analysis, which provided an understanding of the biological functions of coexpressed genes at the cellular level

Summary

Introduction

Alzheimer’s disease (AD), referring to an irreversible neurodegenerative disorder, is manifested in cognitive decline, along with behavioral and psychiatric abnormalities of varying extent [1, 2]. Aβ peptides are derived from the continuous cleavage of amyloid precursor protein (APP) by β- and γ-secretases, known as the amyloidogenic pathway related to neurodegeneration [8, 9] This is in competition with the nonamyloidogenic process of α-secretase cleaving APP that prevents Aβ formation by releasing soluble amyloid precursor protein alpha (sAPPα) [10]. Imbalance of these two pathways leads to Aβ accumulation, which further elicits early synaptic alterations and synaptic loss, a process thought to be regulated by phosphoinositide 3 kinase (PI3K) [11, 12]. The main function of PI3K is to catalyze the phosphorylation of phosphatidylinositol on the 3-hydroxyl group of the Oxidative Medicine and Cellular Longevity (GSE109887)

Methods

Results

Conclusion