Alzheimer’s disease as a co-morbidity of chronic periodontitis with Porphyromonas gingivalis as a causative link between both diseases

A numerous clinical and epidemiological studies show an association between chronic periodontitis and Alzheimer?s disease (AD). AD, the most common form of dementia, is manifested with neuroinflammation consistent with microbiological infection, including microglial activation, inflammasome and complement activation as well as altered cytokine profiles. Infectious agents, including periodontal pathogen Porphyromonas gingivalis (P.g) were identified in the AD patient brains and postulated to be an etiologic factor but causation is still very poorly investigated. In this proposal we seek to examine in detail the comorbidity between PD and AD with special emphasis on the P.g role in the pathogenesis of AD. To this end we will: i) establish a novel, highly sensitive assay allowing for identification of the presence of P.g and/ or its virulence factors in the CNS; ii) identify virulence factors essential for P.g-induced neurodegenerative changes in wild-type mice and different murine models of AD and establish a reliable model for discovery of novel biomarkers;; iii) evaluate the impact of eradication of specific periodontal pathogens on the level of inflammatory markers known to be associated with severity and/or progression of AD; v) employ animal models to provide a proof of concept that oral infection with P.g (experimental PD) impacts (induces and/or accelerates and/or exasperates) AD; vi) use novel, periodontal pathogen-specific antibacterial compounds targeting P.g glutaminyl cyclase (pQC) in the innovative approach to interfere with the assembly of virulence factors and test if they can affect AD development and progression. By casting new light on mechanisms driving comorbidity of PD in AD the completion of the project will pave the way to novel early diagnostic, preventive, therapeutic and monitoring strategies needed for successful management of AD

The international and inter-disciplinary cooperation facilitated by this grant enabled us to describe transcriptomic and proteomic AD-like changes induced by PD. Norwegian group's role in this task has provided the consortium with multi-parametric studies of murine brain macrophages - microglia (line SIM A9) after Porphyromonas gingivalis and Tannerella forsythia challenge. The characteristic populations observed during these studies, particularly in the case of PD-L1-enriched cells, will constitute the foundation for future research and therapies. This is particularly interesting in the context of high CSF PD-L1 detected in AD patients - our work provides another argument for immune checkpoint therapies in neurodegeneration. Next, we have expanded our study by spatial protoemic analyses of brain tissue provided to us by Polish and German teams (wild type and 5xFADD mice), where we have observed significant activation of astrocytes and signs of neovascularisation post oral infection with Porphyromonas gingivalis. These crucial findings will pave way for continuation of research by us and our international partners, further untangling the relationship between the bacteria-driven PD and neuroinflammation. Notably, our studies constitute further proof of P. gingivalis and possibly other PD pathogens influencing the pathogenesis of AD, thus stressing the need to maintain oral health in general population as a preventative and/or disease-modifying measure, as well as improving educational efforts in this regard.

A numerous clinical and epidemiological studies show an association between chronic periodontitis and Alzheimer’s disease (AD). AD, the most common form of dementia, is manifested with neuroinflammation consistent with microbiological infection, including microglial activation, inflammasome and complement activation as well as altered cytokine profiles. Infectious agents, including periodontal pathogen Porphyromonas gingivalis (P.g) were identified in the AD patient brains and postulated to be an etiologic factor but causation is still very poorly investigated. In this proposal we seek to examine in detail the comorbidity between PD and AD with special emphasis on the P.g role in the pathogenesis of AD. To this end we will: i) establish a novel, highly sensitive assay allowing for identification of the presence of P.g and/ or its virulence factors in the CNS; ii) identify virulence factors essential for P.g-induced neurodegenerative changes in wild-type mice and different murine models of AD and establish a reliable model for discovery of novel biomarkers;; iii) evaluate the impact of eradication of specific periodontal pathogens on the level of inflammatory markers known to be associated with severity and/or progression of AD; v) employ animal models to provide a proof of concept that oral infection with P.g (experimental PD) impacts (induces and/or accelerates and/or exasperates) AD; vi) use novel, periodontal pathogen-specific antibacterial compounds targeting P.g glutaminyl cyclase (pQC) in the innovative approach to interfere with the assembly of virulence factors and test if they can affect AD development and progression. By casting new light on mechanisms driving comorbidity of PD in AD the completion of the project will pave the way to novel early diagnostic, preventive, therapeutic and monitoring strategies needed for successful management of AD.