G-4156

Association of Oral-Derived Gingipains and GSK-3β Activation with Amyloid-β and Tau Pathology in Alzheimer Disease:A Systematic Review

 Mohammad Moein Tootestani ¹ © ℗, Shayan Fattahian ², Maryam Dabirifard ³, Mohamadreza Abedzadeh ⁴   

 
Abstract

Introduction: Alzheimer's disease affects over 55 million individuals worldwide, creating a substantial economic burden exceeding $1.3 trillion annually. The pathological hallmarks include amyloid-β plaques and hyperphosphorylated tau tangles that progressively damage neural networks. Recent research has revealed an unexpected connection between oral health and neurodegeneration through Porphyromonas gingivalis-derived enzymes called gingipains. These bacterial proteases—RgpA, RgpB, and Kgp variants—have been detected within Alzheimer's brain tissue and appear to interact with glycogen synthase kinase-3β, a crucial protein governing tau phosphorylation and amyloid processing. However, the mechanistic relationship between gingipains, GSK-3β activation, and subsequent pathological biomarker production remains incompletely understood. This systematic review examined the association between gingipains and GSK-3β in promoting amyloid-β and tau marker accumulation in Alzheimer's disease pathogenesis. Search Strategy: This systematic review followed PRISMA guidelines.we systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library through December 2024. Inclusion criteria comprised studies investigating gingipains and GSK-3β in Alzheimer's contexts, research measuring amyloid-β or tau markers, peer-reviewed English publications, and original research articles. Exclusion criteria included review articles, studies lacking control groups, non-English publications, and investigations with incomplete data. Two independent reviewers screened 2,847 titles and abstracts, evaluating 89 full-text articles for eligibility. Quality assessment utilized Newcastle-Ottawa Scale and Cochrane Risk of Bias tools. Results: Twenty-four studies met inclusion criteria, encompassing 15 in vitro investigations, 7 animal studies, and 2 clinical trials from 1,234 participants. Laboratory studies revealed that gingipain exposure increased GSK-3β activity by 2.4-fold (95% CI: 1.9-3.1, p0.001) and enhanced tau phosphorylation at Ser396 by 185% and Thr231 by 230%. Amyloid-β42 production increased by 68% following gingipain treatment, while clearance mechanisms decreased by 42%. Animal studies demonstrated cerebral gingipain accumulation within 4-6 weeks, accompanied by 3.2-fold GSK-3β upregulation and accelerated plaque formation. Clinical investigations showed significantly elevated gingipain levels in Alzheimer's patients' brain tissue (p=0.002), with strong correlations between gingipain presence and cerebrospinal fluid tau levels (r=0.74, p0.001). These findings suggest therapeutic approaches including gingipain inhibitor development and enhanced periodontal care protocols. Conclusion and Discussion: Our systematic review establishes compelling evidence for mechanistic connections between gingipains and GSK-3β in Alzheimer's disease progression, indicating that periodontal pathogens may significantly contribute to neurodegeneration through enhanced tau hyperphosphorylation and amyloid-β accumulation. These discoveries support developing targeted gingipain inhibitors as novel therapeutic interventions while emphasizing preventive oral health maintenance in Alzheimer's disease management strategies.

Keywords: Alzheimer's disease, GSK-3β, amyloid-β, tau protein, Porphyromonas gingivalis