Identifying candidate gene linking P. Gingivalis to Alzheimer’s Disease: a systematic review, bioinformatic analysis and, zebrafish model validation

Abstract

Porphyromonas gingivalis (P. gingivalis) is a non-motile, rod-shaped, anaerobic Bacteroidetes phylum, and forming black colonies morphology on a blood agar. Periodontitis is a chronic inflammatory periodontal disease leading to the destruction of tooth- supporting tissues and eventual tooth loss. In recent years, several studies have shown an association between periodontitis and other systemic diseases including Alzheimer’s Disease (AD) which is a complex neurodegenerative disorder that poses cognitive ability deterioration including language, memory, comprehension, attention, judgment and reasoning. Studies have implicated P. gingivalis as a potential contributor to the development of AD. However, the precise nature of this relationship remains elusive, necessitating a comprehensive investigation. The main objective of this project is to investigate the relationship between P. gingivalis and AD using various method. firstly, the study employed a systematic review and meta-analysis to identify knowledge gaps and substantiate the association of interest. A bioinformatics analysis was performed using Omnibus and R software to identify differentially expressed common genes. Functional enrichment analysis was conducted, and a Protein-Protein Interaction (PPI) network was constructed to explore gene interactions. The zebrafish model's viability for P. gingivalis-associated AD was assessed by determining the LD50, and performing histological examination using H&E staining. Finally, gene validation was conducted by detecting the presence of WTH3DI, ID3, and VPS33B in zebrafish brain tissue using qPCR. The systematic search across two databases yielded 27 records for further analysis from 112 records in PubMed and 35 from Scopus. A strong positive correlation between P. gingivalis and AD was identified, with a pooled odds ratio of 2.45 (CI: 1.80-3.33). Hazard ratio analysis indicated a higher likelihood of developing AD in individuals infected with P. gingivalis, with a ratio of 1.06 (CI: 1.06-1.11). In silico analysis identified ten common genes linked to both P. gingivalis and AD, including CALD1, HES1, and WTH3DI. The LD50 of P. gingivalis was established at 107 cfu/ml using zebrafish, revealing neuronal degeneration and elevated proinflammatory markers IL-1β and TNF-α. Overall, the study indicates a significant genetic linkage between P. gingivalis and AD, with WTH3DI showing significant changes with p-value <0.05 that further strengthen the association between the two diseases.