NRN1 may Modulate Tau Phosphorylation and Neuronal Apoptosis in AD via the PIGU-CASP3 Axis

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hyperphosphorylation of tau protein to form neurofibrillary tangles (NFTs) and amyloid β (Aβ) deposition to form senile plaques, and its specific regulatory mechanism remains incompletely understood. Neurotrophic factors (NTFs) play important roles in neuronal growth, differentiation, and survival, and are considered to have potential therapeutic effects in AD.

This study aimed to investigate the effects of NTFs on tau protein phosphorylation in AD and its underlying mechanisms.

A correlation analysis was conducted between neurotrophic factors and tau protein phosphorylation genes using bioinformatics analysis. The relationship between the candidate neurotrophic factor NRN1 and tau protein phosphorylation was validated in vivo. The effects of NRN1 on tau protein phosphorylation, neural process-related proteins, and apoptosis were explored in vitro. Subsequently, GO and KEGG pathway enrichment analyses and PPI network were utilized to identify potential functions and pathways, as well as pinpoint core regulatory factors. Finally, the mechanism by which NRN1 affects tau protein phosphorylation was explored through Western blot analysis.

Bioinformatics analysis revealed a significant negative correlation between NRN1 and MAPT, a gene linked to tau protein phosphorylation. Western blot analysis indicated a decrease in NRN1 expression and an increase in p-tau levels in the hippocampus of AD mice. NRN1 significantly reduced the expression of p-tau in AD cell models and enhanced the expression of MAP2, a protein related to neural processes. Further, apoptosis analysis demonstrated that NRN1 significantly decreased the level of cleaved caspase-3 and elevated the Bcl-2/Bax ratio. Bioinformatics analysis and PPI network construction suggested PIGU and CASP3 to play pivotal roles in NRN1 regulation of tau protein phosphorylation.

NRN1 may mitigate tau protein phosphorylation and neuronal apoptosis by modulating the PIGU-CASP3 pathway in AD. This finding offers novel insights into NRN1 as a potential target for the treatment of AD.