Journal Search Engine
Search Advanced Search Adode Reader(link)
Download PDF Export Citaion korean bibliography PMC previewer
ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.46 No.6 pp.111-123

Functional Relationship between Porphyromonas Gingivalis-driven Periodontal Disease and Alzheimer's Dementia

Ka Young Boo1)*, Dae Sol Choi1)*, Hye Won Gwak1)*, Da Eun Jeon1)*, Su Eun Kang1)*, Min Seo Lee1)*, Tae Young Park1)*, Hyeon Ryong Shim1)*, Ji Hye Lee1),2),3),3)
1)Department of Dentistry
2)Department of Oral Pathology
3)Periodontal disease signaling network research center, School of Dentistry
4)Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea

# These authors contributed equally to this manuscript.

* Correspondence: Ji Hye Lee, Department of Oral Pathology School of Dentistry Pusan National University Mulgeum-eup, Yangsan-si 50612. Korea Tel: +82-51-510-8259 Email:
December 6, 2022 December 9, 2022 December 16, 2022


Periodontitis, especially in its chronic form, is one of the leading causes of tooth loss, significantly affecting the quality of life in the modern era of aging society. Recent studies have revealed a potential correlation between periodontitis and various systemic diseases, including cardiovascular diseases and Alzheimer’s dementia (AD). With the body of epidemiologic evidence that links these separate disease entities, several lines of hypotheses have been postulated to provide mechanistic understandings that mostly comprises abnormal regulation of immunologic and inflammatory signaling. In this review, we revisit the experimental findings that describe virulence factors derived from Porphyromonas Gingivalis, including gingipains and lipopolysaccharides, as well as their roles in the pathophysiology of AD. In addition, we address potential immunologic challenges imposed by this bacterial pathogen contributing to progression of AD.

Porphyromonas Gingivalis 관련 치주질환과 알츠하이머성 치매 간의 기능적 상관관계 연구

부 가영1)*, 최 대솔1)*, 곽 혜원1)*, 전 다은1)*, 강 수은1)*, 이 민서1)*, 박 태영1)*, 심 현룡1)*, 이 지혜1),2),3),3)
1)부산대학교 치과대학 치의학과
3)치주질환 신호네트워크 연구센터



    Periodontal disease is an inflammatory disease characterized by periodontal pocket formation, gingival regression, and periodontal ligament and alveolar bone destruction (1). It is a common dental disease that affects nearly 20~50% of global population (2). With the average life expectancy increasing, oral health became a significant issue to improve the quality of life that can be negatively affected by periodontal diseases. Various bacterial risk factors, including Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum and Treponema denticola, are often associated with the development of periodontal disease (3-6).

    Recently, multiple layers of epidemiologic evidence have been provided to demonstrate a significant correlation between periodontal and systemic diseases (3). In line with this idea, the prevalence of periodontal disease is significantly high in patients suffering from various systemic diseases. For instance, patients with Alzheimer’s dementia or disease (AD) also appear to suffer frequently from periodontal disease (7, 8). Such correlation demonstrated by several epidemiologic studies has prompted researchers to explore the molecular links between these rather distinct disease entities.

    While experimental findings to indicate a causal relationship between periodontitis and systemic diseases remain limited, there are some relevant molecular mechanisms postulated based upon in vitro and bioinformatical studies. For instance, bacterial infection can trigger systemic immunologic and inflammatory responses through circulation of pro-inflammatory substances (9). Abnormal regulation of inflammatory signaling is taken as a major factor to consider in the etiology of various systemic diseases, including AD (10). Considering the inflammatory nature of periodontitis, it is thus plausible to postulate a functional link between periodontal and systemic diseases via abnormal immunologic and inflammatory signaling. In this review, we discuss the current understanding of P. gingivalis-derived risk factors that contribute to the pathophysiology of AD responsible for the major cognitive decline occurring in the aged population. We will address relevant issues on P. gingivalis-derived gingipains and lipopolysaccharides, as well as immune evasion strategies employed by this bacterial pathogen.

    Ⅱ. P. gingivalis-induced gingipain as a significant molecular player to accelerate Alzheimer’s dementia

    1. Gingipain as an important exotoxin derived from P. gingivalis

    Gingipain is a potent, protease-based virulence factor that contributes to the pathologic outcomes of P. gingivalis infection (11). The major molecular components of gingipain include a lysine- and two arginine-based gingipains (Kgp and RgpA/B, respectively). Once synthesized within the bacteria, gingipains are transported to the surface of bacterial cytoplasmic membrane and packed into outer membrane vesicles (OMVs) for its extracellular release (11). Gingipains play diverse roles in the biology of P. gingivalis, including survival and maintenance of its pathologic characteristics as well as adherence to host cells and digestion of host proteins. For example, gingipains act as non-fimbrial adhesins to interact with host extracellular matrix proteins such as fibrinogen, fibronectin, laminin and collagen type V. They are also involved in fimbrial maturation during the initial phase of adherence (12).

    2. Host system damage induced by gingipains

    In addition to their role in adherence, gingipains can cause diverse adversary effects on host cells. For example, gingipains function as a potent endopeptidase to digest various serum- and tissue-derived host proteins (13). Furthermore, they participate in the lysis of erythrocytes, followed by their binding to hemoglobin to retrieve heme and iron for their survival (14, 15).

    Gingipains also play a critical role in neutralizing host immune systems. For instance, gingipains interfere with cationic antimicrobial peptides in host mucosal membranes that are responsible for neutralizing bacterial lipopolysaccharides (LPS) as a means of innate defense mechanisms (16, 17). Such failure in LPS neutralization may contribute to prolonged release of pro-inflammatory cytokines. Indeed, gingipains have been suggested to modulate the activities of various cytokines and their receptors, including interleukin- 1b (IL-1b), IL-6, IL-8 and IL-12, all of which would result in disruption of normal host immune responses (18-21).

    In addition to its potential role in host immune regulation, gingipains may also induce apoptosis of host cells by their targeting of cell adhesion molecules. For instance, interference of fibronectin-integrin interaction by Rgp has been reported in human gingival fibroblasts, ultimately resulting in intercellular separation and subsequent cell death (22). Similarly, the cooperative activity between Rgp and Kgp could prevent intercellular adhesion between endothelial cells in human umbilical veins, again contributing to their apoptosis (23). The detailed mechanisms underlying gingipain-induced interference of cell adhesion and host cell death remain poorly understood, awaiting further investigation of molecular events governing these rather distantly related cellular responses.

    3. Gingipain as a contributing factor to Alzheimer’s dementia

    Recent studies in neurodegenerative diseases have suggested a potential contribution of gingipains in development of various neurologic diseases. For instance, it has been proposed that P. gingivalis-derived gingipains may cause neuronal damages underlying the progression of AD. Indeed, a higher level of immune reactivity against gingipains has been identified in the brain tissue of AD patients, along with greater loads of RgpB and Kgp components of gingipains in the cerebrospinal fluid (CSF) when compared with the normal cohorts (24). In addition, a significant association between the loads of gingipains and ubiquitin molecules has been mapped in these pathologic specimens (24). Considering the role of ubiquitin in formation of β-amyloid plaques (β-APs) and neurofibrillary tangles characteristic of AD, it is thus plausible to hypothesize gingipain-induced pathologic cellular responses contributing to development of molecular signatures of AD. In the following section, we will discuss potential molecular mechanisms that link gingipain-induced cellular damages and molecular characteristics of AD.

    Ⅲ. Expression of pathophysiologic hallmarks of Alzheimer’s dementia influenced by gingipains

    1. The β-amyloid plaques as a representative pathophysiologic hallmark of Alzheimer’s dementia

    One of the most extensively studied characteristics of AD at the cellular level involves accumulation of β-APs in the affected brain tissue (25). β-APs represent aggregates of β -amyloid peptides processed from amyloid precursor protein (APP) (26, 27). β-APs represent aggregates of β -amyloid peptides processed from amyloid precursor protein (APP) (28). APP is further processed by the actions of various proteases termed secretases, including α-, β- and γ-subtypes (29).

    Among these proteases, β- and γ-secretases play a critical role in formation of β-amyloid peptide (28). More importantly, integrity of presenilin constituting the catalytic subunit of γ-secretase would dictate the production of either β-amyloid peptide 40 or β-amyloid peptide 42 with two additional C-terminal residues (30, 31). With a trend of significantly promoted aggregation of longer β-amyloid peptides, pathologic conditions subject to the production of β-amyloid peptide 42 would thus favor accumulation of β-APs (30).

    2. Accumulation of the β-amyloid plaques facilitated by gingipains

    Importantly, gingipain can influence formation of β-APs via its regulation of cathepsin B in the host brain. The human cathepsin B encoded by CTSB is a lysosomal cysteine protease that plays an essential role in intracellular proteolysis. More specifically, cathepsin B with high affinity to APP acts as a major β-secretase participating in processing of APP (32, 33). Hook and his colleagues have documented that genetic or pharmacological removal of cathepsin B in the brain could significantly improve memory deficits in mice, presumably via downregulation of β-APs (34-36). These results strongly suggest a positive correlation between the expression level of cathepsin B and accumulation of β-APs.

    A recent report has suggested microglia-dependent upregulation of cathepsin B induced by gingipains (37). In details, gingipain-induced activation of protease-activated receptor 2 (PAR2) triggers transformation of microglia from a resting to activated state, which in turn facilitates NF-ϰB signaling and subsequent accumulation of lysosomal cathepsin B. This process then leads to activation of pro-caspase-1 and its maturation, followed by processing and secretion of IL-1b. Maturation of IL-1b can stimulate production of cathepsin B and APP via its signaling through IL-1 receptors. As a result, cathepsin B-dependent cleavage of APP is further enhanced in the affected brain tissue, with significant accumulation of β-APs (37). Taken together, these cascades of cellular responses may thus indicate gingipains as a potential pathologic factor that contributes to development of β -APs characteristic of AD.

    3. Neurofibrillary tangles and its formation influenced by gingipains

    Along with development of β-APs, formation of neurofibrillary tangles in the brain is considered as another representative hallmark of AD that involves abnormal processing of microtubule-associated tau proteins (25). Tau proteins directly bind to microtubules via their hexapeptide motifs within the microtubule-binding region, including “VQIINK” and “VQIVYK”, thus contributing to the stability of microtubule networks in neurons (1). Gingipain participates in hydrolysis and fragmentation of tau proteins near these hexapeptide motifs, resulting in facilitated formation of paired helical filaments consisting of fragmented tau proteins. Along with subsequent disassembly of microtubule networks, these pathologic changes favor formation of neurofibrillary tangles characteristic of AD, thus further suggesting a role of gingipains as a potential risk factor to facilitate progression of AD (38-41).

    4. Clinical trials of gingipain inhibitors to treat Alzheimer’s dementia

    Previous findings described above consistently indicate development of pathophysiological characteristics of AD significantly influenced by P. gingivalis-derived gingipains, thus allowing researchers to investigate a possibility of gingipain inhibitors as a potential therapeutic targets of AD. Indeed, this issue has been addressed with clinical trials of novel gingipain inhibitors (24). Briefly, we first focus on two inhibitors, COR271 and COR286, irreversibly targeting Kgp and RgpA/B, respectively, and discuss newly developed candidates, COR388 and COR588.

    A 24 hour-long exposure to Kgp and RgpB in neuroblastoma SH-SY5Y cells caused significant cellular aggregation, presumably via the proteolytic activity of gingipains (24). Furthermore, infection of SH-SY5Y cells with the W83 strain of P. gingivalis resulted in approximately 50% of cell death, which was blocked by COR271 and COR286 in a dose-dependent manner (24). These results clearly demonstrate cell-protective effects of these small molecule gingipain inhibitors. In addition, the elevated bacterial DNA load identified in the brain following P. gingivalis infection was successfully reduced by oral administration of COR271 and, in part, by subcutaneous injection of COR286. Subsequent experiments with targeted application of Kgp and RgpB into the hippocampus revealed significant protective effects of a combined application of COR271 and COR286 against gingipain-induced neurodegeneration (24). Similarly, both inhibitors were effective in reducing the loss of GAD67+ interneurons in mice, regardless of a combinatory application of antibiotics (24).

    Based upon the neuroprotective effects of the COR271, its analog was developed, named COR388, with improved penetration ability into the central nervous system (CNS). COR388 was effective in inhibiting the growth of P. gingivalis with no clear sign of resistance developed. Similar to COR271, oral administration of COR388 significantly reduced the bacterial DNA load as well as the levels of β-amyloid peptide 42 (Aβ-42) and inflammatory cytokine such as tumor necrosis factor-α in the infected mouse brain (24). Subsequent Phase 1 trials demonstrated a reduction in the concentration of ApoE in the CSF representative of AD (42). A further clinical investigation using COR388 was completed in January, 2022, while the analysis of primary outcomes still in progress (43). With an initially reported hepatotoxicity and limited effects on cognitive improvement (44), an alternative effort has been made to develop a safer gingipain inhibitor, resulting in another candidate, COR588. The efficacy of COR588 in ameliorating the phenotypes of AD is currently under investigation in a Phase 1 clinical trial (45).

    Ⅳ. Lipopolysaccharide as a significant risk factor to accelerate Alzheimer’s dementia

    1. Lipopolysaccharide as an important endotoxin derived from P. gingivalis

    In addition to gingipains, endotoxins of P. gingivalis can act as significant virulence factor in development and progression of AD. Gram-negative bacteria such as P. gingivalis is protected against environmental factors deleterious for their survival by rigid membrane bilayers consisting of inner and outer membranes (46). Collapse of such protective layers of bacteria leads to a release of various endotoxins that causes infectious phenotypes in the host. One such example of endotoxins is lipopolysaccharide (LPS) that functions as a virulence coat carrying various effector molecules at the cell surface (11). Within the subdomains of LPS, including lipid A, core oligosaccharide and O-antigen, lipid A is considered as a major functional domain in activating immune responses in the host, with its structural variation critical for determining its virulence (47). Recent studies have provided experimental evidence suggesting a potential role of LPS in accelerating the pathogenesis of AD. For instance, P. gingivalis- derived LPS (Pg-LPS) has been detected in the autopsy specimen of brain tissue from AD patients (48). In line with this finding, neurodegenerative features reflecting characteristic pathophysiologic hallmarks of human AD were consistently observed in P. gingivalis- or Pg-LPS-infected mice (49). Taken together, these findings indicate a strong correlation between Pg-LPS and pathophysiology of AD.

    2. Cellular mechanisms underlying lipopolysaccharide-induced microglial damage linked to Alzheimer’s disease

    Cellular mechanisms underlying a functional link between Pg-LPS and AD involve abnormal responses of glial cells in the brain, including microglia and oligodendrocytes. Microglia are the first-in-line players responding to immunologic challenges induced by injuries to the CNS, via dynamic structural and functional transformation during the activation process. Briefly, microglia remain inactivated in a resting, but not dormant, state to monitor potential injuries or infectious pathogens. Once a brain injury is recognized, the level of ATP is increased in the brain parenchymal tissue, which in turn activates microglia to initiate various inflammatory signaling cascades via expression of cell surface receptors and release of inflammatory cytokines (50). Importantly, Pg-LPS could promote microglial activation, as evidenced by apparent expansion of microglial area in the hippocampus of Pg-LPS-infected mice (51) and by in vitro activation of microglia following a treatment of Ultrapure Pg-LPS (52).

    It should be noted that similar modes of microglial activation can be found in neurodegenerative disease states such as AD. For example, neuropathologic signatures of AD are often correlated with activated microglia (53). Recent studies have revealed clustering of activated microglial populations near β-APs (54). In details, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by pattern recognition receptor (PRR) of microglia, which in turn activates NF-ϰB and inflammasomal NLRP3 and subsequently induces release of various cytokines. Activated inflammasomes allow caspase-1 to produce ASC speck that facilitates formation of β-APs through its binding to β-amyloid peptides. In addition, cytokines released from microglia are responsible for neuronal damage and accelerated activation of microglial populations as well as upregulation of APP and β/γ-secretase, altogether to promote formation of β-APs (54-56). These findings collectively suggest a strong correlation between microglial activation and expression of pathophysiological characteristics of AD. Considering the possibility of microglial activation by Pg-LPS, It is thus plausible to hypothesize that Pg-LPS could induce activation of microglia, which in turn accelerate development of AD by promoting accumulation of β-APs.

    3. A novel hypothesis of LPS-induced myelin damage as a potential link between P. gingivalis-derived lipopolysaccharide and Alzheimer’s dementia

    In addition to microglia, LPS can induce damages to other glial cell populations, specifically oligodendrocytes. Myelin synthesized by oligodendrocytes functions as a shield for electrical leakage through neuronal axons, thus ensuring fast conduction of action potentials from the axon hillock to nerve terminals (57). A recent study has reported LPS-induced degradation of myelin basic protein (MBP), a major component constituting myelin structure, as well as colocalization of LPS with degraded MBP (dMBP) and β-APs in the AD brain (48), thus suggesting a potential link between LPS-induced oligodendrocyte damages and AD.

    Elevated levels of dMBP in the AD brain appear to favor accumulation of β-APs, thus facilitating progression of AD (58). While intact MBPs are often located in the boundary of β-APs, dMBP remains in the core of plaques. In addition, the autolytic activity of intact MBP to hydrolyze β-APs is disrupted with dMBP. As a result, elevated levels of β-APs further impair oligodendrocytes to facilitate degradation of MBP, thus promoting a vicious cycle of β-AP accumulation (58). Importantly, oral or subcutaneous infection of P. gingivalis has been reported to induce molecular characteristics of experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis involving abnormal regulation of oligodendrocytes, suggesting potential oligodendrocyte injuries caused by Pg-LPS (59, 60).

    Taken together, these findings strongly suggest that the overall LPS-induced impairment of oligodendrocytes may deregulate the β-AP-related MBP signaling to facilitate progression of AD. The causal relationship between AD and oligodendrocyte dysfunction induced by LPS remains poorly understood, awaiting further investigation to decipher molecular mechanisms underlying the pathophysiology of AD and to provide a valuable insight into development of novel therapeutic remedies.

    Ⅴ. A relationship between immune evasion of P. gingivalis and Alzheimer’s dementia

    1. Immune evasion of infectious pathogens from the host innate immunity

    As described above, P. gingivalis can harm the host nervous system via the actions of gingipain and LPS as well as abnormally regulated inflammatory cytokine responses. However, it is required for infectious pathogens such as P. gingivalis to overcome the host innate immune systems in order to exert their actions. One such innate immune system in the hosts is the skin and mucous membrane that provide physical barriers against intruding reagents. In addition, the host system is equipped with multiple cellular players that mediate various immune responses, including macrophages and neutrophils. For instance, macrophages are the first responder among cellular defense systems that can recognize and capture nearly 100 different antigens until the saturation of their capacity (61). Similarly, neutrophils participate in immune responses within the first 24 to 36 hours, while their remains following apoptosis are still capable of aiding the removal of harmful pathogens via formation of neutrophil extracellular traps (NETs) (61).

    With the presence of these multiple barriers, infectious pathogens have evolved over time to evade killing via host innate immune responses. For instance, with the lack of physical ability to break through the intact tissue barriers, these agents tend to prefer entries through skin injury sites or respiratory droplets, as evidenced by invasion of periodontal microorganisms via intraoral mucosal injury sites (62). Once achieving a successful entry into the host system, bacterial pathogens can evade next-in-line immunologic challenges by releasing molecules that directly mount a counterattack or interfere macrophages and their phagocytic activities. For example, Yersinia pestis introduces specialized proteins into phagocytes to affect their cytoskeletal architecture and thus to prevent morphological changes required for their phagocytic activities (63). In addition, Shigella and Salmonella species can release proteins that bind caspase-1 in the host phagocytic cells, thus inducing their apoptosis (63). In the case of Staphylococcus aureus, the ability of neutrophils to access the site of injury is interrupted via the binding between bacterial proteins and host neutrophil receptors that need to be available for chemoattraction (64).

    2. Complement system as a target of immune evasion by bacterial pathogens

    Another line of host defense against bacterial antigens includes the complement system that consists of more than 30 different components in mammals (65). The action of the complement system starts with opsonization, a process of adherence to antigens, to aid the activity of phagocytes for their recognition and engulfment of antigens. Next, the C3 complex is disassembled into C3a and C3b upon recognition of antigens, followed by inflammatory responses initiated by C3a-dependent stimulation and chemoattraction of phagocytes into the site of injury (65). Finally, the complement system can perform a defensive action independent of other immunologic processes via the activity of the membrane attack complex (MAC). The formation of MAC is initiated upon binding of C3b, a product of C3 hydrolysis with C3 convertases, to other factors, thus generating the C3 convertase complex. Once C5b is subsequently generated via the action of C5 convertases, it forms a MAC complex with C6, C7, C8 and C9 (66). The cascade of these processes occurs simultaneously with numerous complement components attached on the surface of antigens, thus eventually leading to killing of bacterial pathogens.

    Various pathologic microorganisms have evolved molecular mechanisms that could evade such complement-based host defense systems. For instance, Neisseria meningitidis attracts factor H released from human erythrocytes via its factor H-binding protein to prevent the complement system from recognizing them as a bacterial pathogen, thus evading the host innate immunity (67). Similarly, Staphylococcus aureus releases a C3 convertase-binding protein to prevent generation of C3b, thus evading from the initial opsonization process conducted by the host complement system (68).

    3. Immune evasion mechanisms of P. gingivalis

    P. gingivalis employs similar molecular mechanisms to evade the host complement-dependent innate immunity. For instance, it can successfully disrupt formation of MAC in the host by the activity of gingipains to degrade C3 and C5 (62). Gingipains also bind to C4b-binding protein, a potent complement inhibitor, to provide consistent suppression of the complement and lectin pathway activities (69). In addition, P. gingivalis can also evade the host immunity provided by the phagocytic activities of circulating neutrophils or other monocytes. Phagocytic removal of P. gingivalis often depends on the binding of neutrophils or monocytes to C3 protein associated with P. gingivalis. However, this bacterial pathogen can evade phagocytic killing through binding between C3 incorporated on P. gingivalis and CR1 on the erythrocytes. As a result, the uptake of this pathogen by circulating phagocytes is significantly reduced in the host system, with the host erythrocytes acting as a buffer (70). Indeed, binding between P. gingivalis strain and human erythrocytes dramatically inhibited phagocytic uptakes of bacterial pathogens into both neutrophils and monocytes within a minute in vitro (70).

    Additional mode of immune evasion by P. gingivalis is provided by modification of lipid A structure in Pg-LPS, a part responsible for its endotoxic activities (71). Modification in the lipid A structure involves changes in the length of fatty acid chains attached to the core oligosaccharide units. The typical structure of lipid A in Pg-LPS is either in the penta-acylated (LPS1690) or the tetra-acylated form (LPS1435/1449) (72), of which dominance is significantly influenced by the growth conditions. When exposed to an environment rich in hemin following breakdown of host hemoglobin molecules, the lipid A structure in Pg-LPS is shifted from the penta-acylated to tetra-acylated structure that provides a weaker association with the host toll-like receptor type 4 (TLR4) than the former does. As a result, the overall magnitude of TLR4-mediated immune response is significantly reduced in the host, thus facilitating progression of periodontal diseases due to diminished killing of P. gingivalis in the gingival tissue (73).

    4. Evasion of innate immunity by P. gingivalis and Alzheimer’s dementia

    Recent reports based on genome-wide association analyses have strongly suggested the importance of innate immunologic and inflammatory responses in the etiology of AD. The weaker immuno-inflammatory activity against bacterial pathogens due to their immune evasion capacities is thought to favor substantial inflammatory signaling present for a prolonged duration to facilitate development of pathologic hallmarks of AD (10). As described above, P. gingivalis can employ effective strategies to evade multiple layers of host immunologic barriers. While a recent study has suggested suppression of adaptive immunity by P. gingivalis in association with atherosclerosis and AD (74), it remains unclear whether a similar mode of immune evasion in innate immunity is responsible for P. gingivalis-induced progression of AD. Considering the potency and associated complications, immune evasion by P. gingivalis needs to be further elucidated for unknown molecular mechanisms that may significantly affect the progression and prognosis of AD. Future investigations on P. gingivalis-induced immune evasion mechanisms will provide a valuable insight into novel therapeutic agents that effectively target immune evasion- mediated pathogenesis of P. gingivalis infection associated with AD.

    Ⅵ. Conclusion

    In this review, we summarize the current understanding of P. gingivalis-derived virulence factors, including gingi pains and LPS, in the pathogenesis of AD (Figure 1). The pathologic hallmarks of AD appear strongly correlated with expression and potency of these virulence factors. In addition, immune evasion strategies employed by P. gingivalis could potentially influence the progression and pathophysiology of AD by modulating immunologic and inflammatory signaling in the brain parenchymal tissue, ultimately resulting in neuronal dysfunction and cell death (Figure 1). Future experimental efforts will further strengthen a functional relationship established between periodontitis and AD and broaden our scope in understanding the molecular mechanisms that directly link these separate disease entities.


    This work was supported by a 2-Year Research Grant of Pusan National University to Ji Hye Lee.



    P. gingivalis-derived virulence factors and their influences on the pathophysiology of Alzheimer’s dementia.

    The outer membrane vesicles released from P. gingivalis under a periodontal disease condition, deliver two representative virulence factors, gingipains and lipopolysaccharides. These factors can induce significant activation of microglial populations in the brain, thus promoting expression of pathologic hallmarks of Alzheimer’s dementia (AD): accumulation of β-amyloid plaques (β-APs) and formation of neurofibrillary tangles. In addition, they also provide molecular mechanisms to evade the innate immune responses triggered in the host cells, by inhibition of the complement and TLR4 pathway activities.



    1. Sinsky J, Pichlerova K, Hanes J: Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies. Int J Mol Sci 2021;22:17.
    2. Nazir MA:Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci (Qassim) 2017;11:72-80.
    3. Kim J, Amar S: Periodontal disease and systemic conditions: a bidirectional relationship. Odontology 2006;94:10-21.
    4. Hajishengallis G, Chavakis T: Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 2021;21: 426-440.
    5. How KY, Song KP, Chan KG: Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line. Front Microbiol 2016;7:53.
    6. Fong SB, Boyer E, Bonnaure-Mallet M, Meuric V: Microbiota in Periodontitis: Advances in the Omic Era. Adv Exp Med Biol 2022;1373:19-43.
    7. Yadav P, Lee YH, Panday H, Kant S, Bajwa N, Parashar R: Implications of Microorganisms in Alzheimer's Disease. Curr Issues Mol Biol 2022;44: 4584-4615.
    8. Mao S, Huang CP, Lan H, Lau HG, Chiang CP, Chen YW: Association of periodontitis and oral microbiomes with Alzheimer's disease: A narrative systematic review. J Dent Sci 2022;17:1762-1779.
    9. Bhuyan R, Bhuyan SK, Mohanty JN, Das S, Juliana N, Juliana IF: Periodontitis and Its Inflammatory Changes Linked to Various Systemic Diseases: A Review of Its Underlying Mechanisms. Biomedicines 2022;10:10.
    10. Olsen I, Singhrao SK: Inflammasome Involvement in Alzheimer's Disease. J Alzheimers Dis 2016;54: 45-53.
    11. Lunar Silva I, Cascales E: Molecular Strategies Underlying Porphyromonas gingivalis Virulence J Mol Biol 2021;433:166836.
    12. Nakayama K, Yoshimura F, Kadowaki T, Yamamoto K: Involvement of arginine-specific cysteine proteinase (Arg-gingipain) in fimbriation of Porphyromonas gingivalis. J Bacteriol. 1996;178: 2818-2824.
    13. Grenier D, Roy S, Chandad F, Plamondon P, Yoshioka M, Nakayama K: Effect of inactivation of the Arg- and/or Lys-gingipain gene on selected virulence and physiological properties of Porphyromonas gingivalis. Infect Immun 2003;71:4742-4748.
    14. Lewis JP, Dawson JA, Hannis JC, Muddiman D, Macrina FL: Hemoglobinase activity of the lysine gingipain protease (Kgp) of Porphyromonas gingivalis W83. J Bacteriol 1999;181:4905-4913.
    15. Paramaesvaran M, Nguyen KA, Caldon E, McDonald JA, Najdi S, Gonzaga G: Porphyrin-mediated cell surface heme capture from hemoglobin by Porphyromonas gingivalis. J Bacteriol 2003;185: 2528-37.
    16. Koziel J, Karim AY, Przybyszewska K, Ksiazek M, Rapala-Kozik M, Nguyen KA: Proteolytic inactivation of LL-37 by karilysin, a novel virulence mechanism of Tannerella forsythia. J Innate Immun. 2010;2: 288-293.
    17. Guo Y, Nguyen KA, Potempa J: Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000 2010;54:15-44.
    18. Sharp L, Poole S, Reddi K, Fletcher J, Nair S, Wilson M: A lipid A-associated protein of Porphyromonas gingivalis, derived from the haemagglutinating domain of the RI protease gene family, is a potent stimulator of interleukin 6 synthesis. Microbiology (Reading). 1998;144 (Pt 11): 3019-3926.
    19. Banbula A, Bugno M, Kuster A, Heinrich PC, Travis J, Potempa J: Rapid and efficient inactivation of IL-6 gingipains, lysine- and arginine-specific proteinases from Porphyromonas gingivalis. Biochem Biophys Res Commun 1999;261:598-602.
    20. Mikolajczyk-Pawlinska J, Travis J, Potempa J: Modulation of interleukin-8 activity by gingipains from Porphyromonas gingivalis: implications for pathogenicity of periodontal disease. FEBS Lett 1998;440:282-286.
    21. Yun PL, Decarlo AA, Collyer C, Hunter N: Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis. Infect Immun. 2001;69: 5650-5660.
    22. Baba A, Abe N, Kadowaki T, Nakanishi H, Ohishi M, Asao T: Arg-gingipain is responsible for the degradation of cell adhesion molecules of human gingival fibroblasts and their death induced by Porphyromonas gingivalis. Biol Chem 2001;382:817-824.
    23. Kobayashi-Sakamoto M, Hirose K, Nishikata M, Isogai E, Chiba I: Osteoprotegerin protects endothelial cells against apoptotic cell death induced by Porphyromonas gingivalis cysteine proteinases. FEMS Microbiol Lett 2006;264:238-245.
    24. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A: Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 2019;5(1):eaau3333.
    25. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet 2011;377: 1019-1031.
    26. Dickson DW: The pathogenesis of senile plaques. J Neuropathol Exp Neurol 1997;56:321-339.
    27. Walker LC: Abeta Plaques. Free Neuropathol 2020;1.
    28. Haass C, Kaether C, Thinakaran G, Sisodia S: Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2012;2:a006270.
    29. Zheng H, Koo EH: The amyloid precursor protein: beyond amyloid. Mol Neurodegener 2006;1:5.
    30. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA,: Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 2004;13:159-170.
    31. Gu L, Guo Z: Alzheimer's Abeta42 and Abeta40 peptides form interlaced amyloid fibrils. J Neurochem. 2013;126: 305-311.
    32. Hook V, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J: Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta- secretase of Alzheimer's disease. Biol Chem. 2005;386: 931-940.
    33. Hook V, Schechter I, Demuth HU, Hook G: Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease. Biol Chem 2008;389: 993-1006.
    34. Hook VY, Kindy M, Hook G: Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J Biol Chem 2008;283:7745-7753.
    35. Hook G, Hook V, Kindy M: The cysteine protease inhibitor, E64d, reduces brain amyloid-beta and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, beta-secretase activity. J Alzheimers Dis 2011;26: 387-408.
    36. Hook VY, Kindy M, Reinheckel T, Peters C, Hook G: Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochem Biophys Res Commun 2009;386:284-288.
    37. Nakanishi H, Nonaka S, Wu Z: Microglial Cathepsin B and Porphyromonas gingivalis Gingipains as Potential Therapeutic Targets for Sporadic Alzheimer's Disease. CNS Neurol Disord Drug Targets 2020;19:495-502.
    38. Wang JZ, Xia YY: Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 2013;33 Suppl 1:S123-39.
    39. Goedert M, Spillantini MG: Propagation of Tau aggregates. Mol Brain. 2017;10:18.
    40. Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X: Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends Mol Med. 2005;11: 164-169.
    41. Kanagasingam S, Chukkapalli SS, Welbury R, Singhrao SK: Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer's Disease. J Alzheimers Dis Rep 2020;4:501-511.
    42. Identifier: NCT03418688. A Multiple Ascending Dose Study of COR388. Bethesda (MD):National Library of Medicine (US) Available at: https://clinicaltrialsgov/ct2/show/NCT03418688. 2022.
    43. Identifier: NCT03823404. GAIN Trial: Phase 2/3 Study of COR388 in Subjects With Alzheimer’s Disease. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrialsgov/ct2/show/NCT03823404. 2019.
    44. Sabbagh MN, Decourt B: COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease. Expert Opin Investig Drugs. 2022;31:987-993.
    45. Identifier: NCT04920903. A Single and Multiple Ascending Dose Study of COR588. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrialsgov/ct2/show/NCT04920903. 2022.
    46. Okamura H, Hirota K, Yoshida K, Weng Y, He Y, Shiotsu N: Outer membrane vesicles of Porphyromonas gingivalis: Novel communication tool and strategy. Jpn Dent Sci Rev 2021;57:138-146.
    47. Schromm AB, Brandenburg K, Loppnow H, Moran AP, Koch MH, Rietschel ET: Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion. Eur J Biochem. 2000;267:2008-13.
    48. Zhan X, Stamova B, Sharp FR: Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review. Front Aging Neurosci. 2018;10:42.
    49. Costa MJF, de Araujo IDT, da Rocha Alves L, da Silva RL, Dos Santos Calderon P, Borges BCD: Relationship of Porphyromonas gingivalis and Alzheimer's disease: a systematic review of pre-clinical studies. Clin Oral Investig. 2021;25:797-806.
    50. Thompson KK, Tsirka SE. The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity. Int J Mol Sci 2017; 18:3.
    51. Pang Y, Dai X, Roller A, Carter K, Paul I, Bhatt AJ: Early Postnatal Lipopolysaccharide Exposure Leads to Enhanced Neurogenesis and Impaired Communicative Functions in Rats. PLoS One. 2016;11:e0164403.
    52. Memedovski Z, Czerwonka E, Han J, Mayer J, Luce M, Klemm LC: Classical and Alternative Activation of Rat Microglia Treated with Ultrapure Porphyromonas gingivalis Lipopolysaccharide In Vitro. Toxins (Basel). 2020;12:5.
    53. Hansen DV, Hanson JE, Sheng M: Microglia in Alzheimer's disease. J Cell Biol. 2018;217:459-472.
    54. Leng F, Edison P: Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 2021;17:157-172.
    55. Alasmari F, Alshammari MA, Alasmari AF, Alanazi WA, Alhazzani K.:Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism. Biomed Res Int 2018;2018: 3087475.
    56. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW: Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 2008;5:37.
    57. Simons M, Nave KA: Oligodendrocytes: Myelination and Axonal Support. Cold Spring Harb Perspect Biol 2015;8: a020479.
    58. Zhan X, Jickling GC, Ander BP, Stamova B, Liu D, Kao PF: Myelin basic protein associates with AbetaPP, Abeta1-42, and amyloid plaques in cortex of Alzheimer's disease brain. J Alzheimers Dis 2015;44:1213-1229.
    59. Polak D, Shmueli A, Brenner T, Shapira L: Oral infection with P. gingivalis exacerbates autoimmune encephalomyelitis. J Periodontol 2018;89:1461- 1466.
    60. Shapira L, Ayalon S, Brenner T: Effects of Porphyromonas gingivalis on the central nervous system: activation of glial cells and exacerbation of experimental autoimmune encephalomyelitis. J Periodontol. 2002;73:511-516.
    61. Turvey SE, Broide DH: Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24-32.
    62. Singhrao SK, Harding A, Poole S, Kesavalu L, Crean S: Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer's Disease. Mediators Inflamm. 2015;2015:137357.
    63. Finlay BB, McFadden G: Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell. 2006;124:767-782.
    64. de Haas CJ, Veldkamp KE, Peschel A, Weerkamp F, Van Wamel WJ, Heezius EC: Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agent. J Exp Med. 2004;199:687-695.
    65. Taylor P, Botto M, Walport M: The complement system. Curr Biol. 1998;8:R259-61.
    66. Podack ER, Esser AF, Biesecker G, Muller-Eberhard HJ: Membrane attack complex of complement: a structural analysis of its assembly. J Exp Med. 1980;151: 301-313.
    67. Rooijakkers SH, van Strijp JA: Bacterial complement evasion. Mol Immunol. 2007;44(1-3):23-32.
    68. Rooijakkers SH, Ruyken M, Roos A, Daha MR, Presanis JS, Sim RB: Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat Immunol 2005;6: 920-927.
    69. Potempa M, Potempa J, Okroj M, Popadiak K, Eick S, Nguyen KA, et al. Binding of complement inhibitor C4b-binding protein contributes to serum resistance of Porphyromonas gingivalis. J Immunol 2008;181: 5537-5544.
    70. Belstrom D, Holmstrup P, Damgaard C, Borch TS, Skjodt MO, Bendtzen K: The atherogenic bacterium Porphyromonas gingivalis evades circulating phagocytes by adhering to erythrocytes. Infect Immun 2011;79:1559-1565.
    71. Olsen I, Singhrao SK: Importance of heterogeneity in Porhyromonas gingivalis lipopolysaccharide lipid A in tissue specific inflammatory signalling. J Oral Microbiol 2018;10: 1440128.
    72. Herath TD, Wang Y, Seneviratne CJ, Darveau RP, Wang CY, Jin L: The expression and regulation of matrix metalloproteinase- 3 is critically modulated by Porphyromonas gingivalis lipopolysaccharide with heterogeneous lipid A structures in human gingival fibroblasts. BMC Microbiol 2013;13:73.
    73. Herath TD, Darveau RP, Seneviratne CJ, Wang CY, Wang Y, Jin L: Tetra- and penta-acylated lipid A structures of Porphyromonas gingivalis LPS differentially activate TLR4-mediated NF-kappaB signal transduction cascade and immuno-inflammatory response in human gingival fibroblasts. PLoS One 2013;8:e58496.
    74. Olsen I, Taubman MA, Singhrao SK. Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer's disease. J Oral Microbiol 2016;8:33029.
    오늘하루 팝업창 안보기 닫기