Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent

Díaz‐Zúñiga, Jaime; More, Jamileth; Melgar‐Rodríguez, Samanta; Jiménez-Unión, Matías; Villalobos-Orchard, Francisca; Muñoz‐Manríquez, Constanza; Monasterio, Gustavo; Valdés, José Luís; Vernal, Rolando; Paula-Lima, Andrea

doi:10.3389/fimmu.2020.588036

Cited by 44 publications

(71 citation statements)

References 91 publications

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“…However, in db/db mice, the classical AD Aβ plaques and NFT formation were not observed in the hippocampus or any other anatomical regions of the brain following the silver impregnation of tissue sections. Regarding anti-tau immunostaining, our observations are similar to the Díaz-Zúñiga et al [14] study in which oral infections of rats with several capsular P. gingivlis strains of variable serotypes and virulence showed the absence of the classical AD Aβ plaques shown by Ilievski et al [29]. An underlying reason behind the lack of Aβ deposition in the present study could be that the mice were obese and of diabetic dispostionand not of healthy wild-type phenotype.…”

Section: Discussionsupporting

confidence: 91%

“…The insoluble Aβ deposition and the development of NFT tau protein have a direct connection with the intracerebral innate immune response and complement activation [11]. Progression and development of Aβ links with microbial infections [12,13], and the inflammatory mediator (cytokines) release that always follows the microbial entry into the host [3,14]. While the role of P. gingivalis infection in the development of Aβ deposits is unfolding, it is unclear how the amyloid precursor protein (APP) processing could lead to Aβ deposition.…”

Section: Introductionmentioning

confidence: 99%

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Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Bahar

Kanagasingam

Tambuwala

et al. 2021

JAD

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Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer’s disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Bahar

Kanagasingam

Tambuwala

et al. 2021

JAD

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“…Alzheimer’s disease is characterized by the presence of extracellular senile plaques of the amyloid-beta (Aβ) aggregated protein, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and neuroinflammation ( De-Paula et al, 2012 ; Cheng et al, 2018 ; Bouteiller et al, 2019 ; Castellani et al, 2019 ; Diaz-Zuniga et al, 2020 ). Senile plaques are composed of Aβ peptides generated after amyloid precursor protein (APP) proteolysis through the amyloidogenic pathway ( Chow et al, 2010 ).…”

Section: Pkr Role In Age-related Neurodegenerative Diseasesmentioning

confidence: 99%

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

Martinez

Gómez

Matus

2021

Front. Aging Neurosci.

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There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

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“…A number of studies have reported an association between periodontitis and AD [19][20][21][22][23][24][25][26][27][28]. Several reports have suggested how virulence factors of P. gingivalis can contribute to AD, particularly LPS, gingipains, PPAD (P. gingivalis peptidylarginine deiminase), Mfa1 fimbrial protein, BCAT (branched-chain amino acid aminotransferase), and capsular polysaccharides [29][30][31][32][33][34]. P. gingivalis and its gingipains were detected in the brains of AD patients [22].…”

Section: Relationship Between Periodontitis and Alzheimer's Diseasementioning

confidence: 99%

“…Therefore, brain inflammation due to P. gingivalis could be an early event that explains the pathology found in middleaged individuals before cognitive decline appears [22]. It is also likely that P. gingivalis contributes to intracerebral and systemic A␤ production [33,48].…”

Section: Amyloid-␤ Occurs In the Brain Of Both Healthy And Ad Peoplementioning

confidence: 99%

Can Porphyromonas gingivalis Contribute to Alzheimer’s Disease Already at the Stage of Gingivitis?

Olsen

2021

ADR

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Alzheimer’s disease (AD) has been associated with periodontitis, which starts as gingivitis. Similar to periodontitis, gingivitis bacteria, bacterial products, and inflammatory mediators can travel to the brain via the blood stream and promote brain inflammation. Periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, both associated with AD, have been found in dental plaque of children already at the age of 3. It is suggested that these bacteria during long-term exposure may drive microglia (brain resident macrophage cells) into a pro-inflammatory M1 phase where they contribute to AD rather than protect against it. This notion comes from studies in mice showing that microglia actually can “remember” previous inflammatory challenge and become “trained” or “tolerant” to toxins like lipopolysaccharide. If gingivitis has an impact on AD, which should be verified, AD prophylaxis should start already at this pre-periodontitis stage with removal of supragingival plaque.

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Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent

Cited by 44 publications

References 91 publications

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

Can Porphyromonas gingivalis Contribute to Alzheimer’s Disease Already at the Stage of Gingivitis?

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