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

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.

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“…PIK3CB has been associated with insulin resistance and hepatic glucose production according to promoter variants [20][21][22]. The expression of PIK3CB is downregulated in patients with AD and linked to the apoptosis and axon guidance pathways [23]. PIK3CB is also genetically associated with mild cognitive impairment (MCI) showing abnormalities in temporal lesions that modulate memory function [24].…”

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“…PIK3CB is significantly downregulated in AD patients compared to controls, suggesting its potential involvement in the disease's progression 112 . The PI3K/AKT pathway, in which PIK3CB is a crucial component, is essential for cell survival, autophagy, neurogenesis, neuronal proliferation, differentiation, and synaptic plasticity, all of which are critical for maintaining cognitive function and neuronal health 113 .…”