Neural Stem Cell (NSC) Secretome and Wnt/β-catenin Signaling Pathway in Alzheimer’s Disease (AD): A Systematic Literature Review and Bioinformatics Analysis

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by neuronal loss, synaptic dysfunction, and cognitive impairment, with no current cure (DeTure & Dickson, 2019; Kumar et al., 2023). The Wnt/β-catenin signaling pathway plays a crucial role in neurogenesis and synaptic plasticity; however, its dysregulation in AD, due to pathological factors such as amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), contributes to disease progression (Jia et al., 2019; Priya et al., 2024). Neural stem cell (NSC) secretome, a collection of bioactive molecules secreted by NSCs, has shown potential in activating the Wnt/β-catenin signaling pathway and promoting neurogenesis in AD (Bahlakeh et al., 2022; Hijroudi et al., 2022). However, the specific components within the NSC secretome that contribute to Wnt/β- catenin activation and their underlying mechanisms remain unknown. This study aimed to identify the components of the NSC secretome, specifically growth factors and neurotrophic factors, that are responsible for activating the Wnt/β-catenin signaling pathway in AD, thereby enhancing neurogenesis, and to investigate their potential mechanisms of action through a comprehensive literature review and bioinformatics analysis. A systematic literature review identified eight growth factors – epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), fibroblast growth factor 8 (FGF8), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), platelet- derived growth factor (PDGF), stem cell factor (SCF), vascular endothelial growth factor (VEGF) – and three neurotrophic factors – brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) – within the NSC secretome that may contribute to Wnt/β-catenin activation in AD. Bioinformatics analysis categorized these proteins using UniProt database, assessed their molecular and biological functions through Gene Ontology (GO) analysis using PANTHER database, and identified their pathway involvement through KEGG database. STRING-based protein-protein analysis (PPI) network analysis provided insight into the intricate crosstalk between PI3K/Akt, MAPK/ERK, and Wnt/β-catenin signaling pathways. Then a targeted literature review was conducted to validate bioinformatics predictions, identifying two direct and one indirect crosstalk mechanism of Wnt/β-catenin signaling pathway activation. The first direct mechanism involves growth factors and neurotrophic factors activating the PI3K/Akt signaling pathway, leading to Akt-mediated phosphorylation and inhibition of glycogen synthase kinase-3β (GSK-3β), which stabilizes β-catenin and promotes its nuclear translocation to activate Wnt target genes. The second direct mechanism involves EGF binding to epidermal growth factor receptor (EGFR) triggering MAPK/ERK activation, where extracellular signal-regulated kinase (ERK) phosphorylates casein kinase 2 (CK2), which subsequently phosphorylates α- catenin. This phosphorylation event disrupts the β-catenin-E-cadherin complex, allowing β-catenin to dissociate and translocate into the nucleus to drive Wnt target gene transcription. The indirect mechanism involves MAPK/ERK signaling activation by growth factors and neurotrophic factors, where rat sarcoma (Ras) activation converts phosphatidylinositol 4,5-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), reinforcing PI3K/Akt pathway activation and enhancing β-catenin stabilization. A final pathway interaction map was constructed to visualize the complex interplay between these signaling pathways and their potential therapeutic implications in AD. Collectively, these findings highlight the potential of NSC secretome components in restoring Wnt/β-catenin signaling in AD through intracellular crosstalk with PI3K/Akt and MAPK/ERK signaling pathway. This study provides a molecular framework for future exploration of NSC secretome-based therapies in AD.