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Abstract

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic dysfunction and the accumulation of amyloid plaques. The molecular mechanisms linking gene dysregulation, pathogenic variants, and protein interaction networks to these core pathologies remain incompletely understood. This study aimed to integrate transcriptomic data with mutation and structural modeling to uncover disease mechanisms and identify therapeutic targets.

Methods

We performed differential gene expression analysis on the GSE138260 microarray dataset using GEO2R to identify DEGs in AD brain tissue. Missense mutations in DEGs were retrieved from the Alzheimer’s Disease Variant Portal (ADVP). Protein-protein interaction networks were constructed using the STRING database to identify connections with the amyloid precursor protein (APP). Molecular dynamics simulations were conducted to evaluate the structural consequences of the BDNF V66M mutation.

Results

A total of 1,588 DEGs were identified, including upregulation of immune-related genes and downregulation of neuroplasticity-associated genes ( BDNF, GRIN2B, GRM8). PPI analysis revealed a core network centered on APP, including BDNF as a direct interactor. The V66M variant in BDNF, confirmed to be downregulated in AD brains, showed increased rigidity and localized flexibility in structural models.

Discussion

The integration of transcriptomics and protein modeling revealed a critical link between BDNF dysfunction and APP interaction in AD. The V66M mutation was found to structurally alter BDNF, potentially disrupting its neuroprotective roles. The findings suggested that impaired BDNF signaling, driven by transcriptional repression and structural mutation, contributes to amyloid pathology and synaptic failure.

Conclusion

This multi-omics investigation has identified BDNF as a converging point of gene dysregulation and pathogenic mutation within an APP-centric network. Structural alterations induced by the V66M mutation may exacerbate amyloid accumulation and neuronal dysfunction, supporting therapeutic strategies aimed at enhancing BDNF signaling in AD.

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2025-10-15
2025-12-15

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An In silico Multi-Omics Investigation of Alzheimer's Disease Linking Gene Dysregulation, Mutations, and Protein Networks to Core Pathologies
Bentham Science Publishers ; https://doi.org/10.2174/0115672050410268250919050955
/content/journals/car/10.2174/0115672050410268250919050955
/content/journals/car/10.2174/0115672050410268250919050955
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  • Article Type:     Research Article
Keywords: Alzheimer's disease (AD) ; brain-derived neurotrophic factor (BDNF) ; in silico analysis ; bioinformatics ; molecular dynamics simulations ; neuroplasticity ; V66M mutation

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