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Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice.

ABSTRACT: Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as Porphyromonas gingivalis. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer's disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD. Cognitive function was significantly impaired in periodontitis-induced APP-Tg mice, compared to that in control APP-Tg mice. Levels of Amiloid β (Aβ) deposition, Aβ40, and Aβ42 in both the hippocampus and cortex were higher in inoculated APP-Tg mice than in control APP-Tg mice. Furthermore, levels of IL-1β and TNF-α in the brain were higher in inoculated mice than in control mice. The levels of LPS were increased in the serum and brain of P. gingivalis-inoculated mice. P. gingivalis LPS-induced production of Aβ40 and Aβ42 in neural cell cultures and strongly enhanced TNF-α and IL-1β production in a culture of microglial cells primed with Aβ. Periodontitis evoked by P. gingivalis may exacerbate brain Aβ deposition, leading to enhanced cognitive impairments, by a mechanism that involves triggering brain inflammation.

SUBMITTER: Ishida N

PROVIDER: S-EPMC5673943 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice.

Ishida Naoyuki N Ishihara Yuichi Y Ishida Kazuto K Tada Hiroyuki H Funaki-Kato Yoshiko Y Hagiwara Makoto M Ferdous Taslima T Abdullah Mohammad M Mitani Akio A Michikawa Makoto M Matsushita Kenji K

NPJ aging and mechanisms of disease 20171106

Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as <i>Porphyromonas gingivalis</i>. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer's disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by <i>P. gingivalis</i> modulates the pat ...[more]

PMID: 29134111

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Project description:Periodontitis exacerbates Alzheimer's disease (AD) through multiple pathways. Both periodontitis and AD are intricately correlated to intestinal homeostasis, yet there is still a lack of direct evidence regarding whether periodontitis can regulate the progression of AD by modulating intestinal homeostasis. The current study induced experimental periodontitis in AD mice by bilaterally ligating the maxillary second molars with silk and administering Pg-LPS injections in APPswe/PS1ΔE9 (APP/PS1) mice. Behavioral tests and histological analyses of brain tissue were conducted after 8 weeks. Gut microbiota was analyzed and colon tissue were also evaluated. Then, fecal microbiota from mice with periodontitis was transplanted into antibiotic-treated mice to confirm the effects of periodontitis on AD and the potential mechanism was explored. The results indicated periodontitis exacerbated cognitive impairment and anxious behaviour in APP/PS1 mice, with increased Aβ deposition, microglial overactivation and neuroinflammation in brain. Moreover, the intestinal homeostasis of AD mice was altered by periodontitis, including affecting gut microbiota composition, causing colon inflammation and destroyed intestinal epithelial barrier. Furthermore, AD mice that underwent fecal transplantation from mice with periodontitis exhibited worsened AD progression and disrupted intestinal homeostasis. It also impaired intestinal barrier function, elevated peripheral inflammation, damaged blood-brain barrier (BBB) and caused neuroinflammation and synapses impairment. Taken together, the current study demonstrated that periodontitis could disrupt intestinal homeostasis to exacerbate AD progression potential via causing gut microbial dysbiosis, intestinal inflammation and intestinal barrier impairment to induce peripheral inflammation and damage BBB, ultimately leading to neuroinflammation and synapse impairment. It underscores the importance of maintaining both periodontal health and intestinal homeostasis to reduce the risk of AD.

Project description:A growing body of literature has identified periodontal disease among the modifiable risk factors for Alzheimer's disease (AD), but the mechanisms underlying this relationship is unknown. This study investigated this relationship using a ligature-induced preclinical periodontitis (Pd) model in non-transgenic (non-Tg) and 3xTg-AD mice. We found that ligature placement caused significant alveolar bone loss, with 3xTg-AD mice exhibiting exacerbated bone loss, suggesting AD-related genetic risk may amplify disease progression. Pd induced robust local inflammatory gene expression in both genotypes, but 3xTg-AD mice indicated a dysregulated immune response. Cognitive deficits were observed only in Pd-afflicted 3xTg-AD mice, specifically in hippocampus-mediated spatial memory and perirhinal cortex-mediated object recognition memory, while non-Tg mice remained unaffected. Neuroinflammatory responses varied by brain region, with the hippocampus and prefrontal cortex (PFC) showing the most pronounced changes. In these regions, 3xTg-AD mice exhibited significantly altered cytokine gene expression compared to non-Tg mice, particularly at later time points. Synaptic markers revealed vulnerabilities in 3xTg-AD mice, including reduced baseline Syp expression and dysregulated Synpo post-ligature. Pd transiently reduced glutamate receptor gene expression in both genotypes, with non-Tg mice showing persistent changes, potentially linked to preserved memory. Pd also accelerated amyloid-β (Aβ) deposition and sustained neurodegeneration in 3xTg-AD mice. Overall, this study shows that combining Pd and AD-related genetic risk exacerbates inflammation, cognitive impairment, synaptic dysfunction, Aβ pathology, and neurodegeneration. Neither insult alone was sufficient to produce these effects, highlighting the synergistic impact. These findings emphasize the need to explore anti-inflammatory interventions and downstream mechanisms to mitigate the confluence of these diseases.

Project description:We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer's disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer's disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer's disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer's disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer's disease with systemic infection. Cerebral hypoperfusion-indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)-and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer's disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-β42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer's disease, and with infection (even in Braak stage 0-II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer's disease; these were related to amyloid-β level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood-brain barrier leakiness associated with Alzheimer's disease and vascular dementia, independently of the level of insoluble amyloid-β, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

Dataset Information

Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice.

Publications

Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice.

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