Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.
Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Manipal, IN · Author affiliation
Department of Biosciences, Manipal University, Jaipur Jaipur-Ajmer Express Highway, Dehmi Kalan, Near GVK Toll Plaza, Jaipur, Rajasthan, 303007, India.Location evidence
Jaipur, IN · Author affiliation
Department of Biosciences, Manipal University, Jaipur Jaipur-Ajmer Express Highway, Dehmi Kalan, Near GVK Toll Plaza, Jaipur, Rajasthan, 303007, India.Location evidence
Greater Noida, IN · Author affiliation
Department of Biotechnology, Noida Institute of Engineering & Technology, Plot No. 19, Knowledge Park-II, Greater Noida, 201306, India.Location evidence
Dehradun, IN · Author affiliation
Department of Biotechnology Graphic Era (Deemed to be University), Dehradun, Uttarakhand, India. Electronic address: sabhi5061@gmail.com.Location evidence
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Original abstract
Chronic periodontitis, driven by Porphyromonas gingivalis, has emerged as a modifiable risk factor for the two most prevalent neurodegenerative disorders includingAlzheimer's disease (AD) and Parkinson's disease (PD), through systemic dissemination of its signature cysteine proteases, gingipains (RgpA, RgpB, Kgp). This review is explicitly scoped to AD and PD, the only neurodegenerative conditions for which the postmortem detection of gingipains in affected brain regions, mechanistic evidence from cellular and animal models, and clinical epidemiological data currently exists in sufficient depth to support an integrated synthesis. Robust meta-analyses confirmed that periodontitis is associated with elevated AD/PD risk (OR/HR 1.2-3.5), while gingipains have been detected in a high proportion (>85-90%) of postmortem AD/PD brains, correlating with tau/α-synuclein pathology, neuroinflammation, and neuronal loss. Mechanistic studies in cellular and animal models have demonstrated that gingipains can disrupt blood-brain barrier integrity via tight-junction cleavage, trigger NF-κB/NLRP3-driven glial activation, catalyse amyloid-β/α-synuclein seeding, induce tau truncation/hyperphosphorylation, and precipitate mitochondrial oxidative damage, which thereby triggers self-amplifying neurotoxic cascades. Salivary gingipain activity offers a non-invasive, high-sensitivity biomarker candidate for early risk stratification that may outperform conventional fluid markers in prodromal cohorts. Therapeutically, small-molecule gingipain inhibitors have shown neuroprotective effects in preclinical models, such as atuzaginstat/COR388 failed primary endpoints in the Phase 2/3 GAIN trial but demonstrated subgroup benefits in P. gingivalis-positive participants; while the next-generation inhibitor LHP588 is advancing in the Phase 2 SPRING trial. Emerging approaches including nanotechnology, CRISPR-based virulence gene disruption, and targeted delivery platforms aim to improve brain exposure and specificity. This review provides an integrated, isoform-resolved framework linking gingipain structure-function to neurodegeneration. Though the associative and mechanistic evidence is compelling, yet definitive causation in humans and disease-modifying efficacy require further validation through biomarker-guided clinical trials. Precision inhibition of gingipains represents a promising upstream strategy for addressing a potentially modifiable microbial contributor at the oral-brain interface.