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A Mouse Model for Pathogen-induced Chronic Inflammation at Local and Systemic Sites
Published on: August 8, 2014
Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages
Ran Nie1, Zhou Wu2,3, Junjun Ni2
1Department of Dental Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China.
Abstract:
Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer's disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770, CatB, Aβ1-42, and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB significantly inhibited the P. gingivalis-induced expression of IL-1β, AβPP770, Aβ1-42, and Aβ3-42 in RAW264.7 cells. Aβ3-42, but not Aβ1-42, induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42. Additionally, the expression of AβPP770, CatB, Aβ1-42, and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κB signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression.
Insights
Chronic Porphyromonas gingivalis infection, linked to periodontitis, drives amyloid-beta (Aβ) accumulation in the brain by affecting macrophages. Targeting Cathepsin B (CatB) may prevent Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation in the brain.
- Porphyromonas gingivalis (P. gingivalis), associated with periodontitis, is increasingly linked to systemic inflammation and neurological conditions.
- The role of P. gingivalis infection in peripheral Aβ metabolism and its contribution to brain Aβ deposition remains unclear.
Purpose of the Study:
- To investigate how chronic systemic P. gingivalis infection influences peripheral Aβ metabolism.
- To determine if P. gingivalis infection expands Aβ pools in inflammatory tissues, contributing to brain Aβ accumulation.
- To explore the therapeutic potential of targeting specific pathways involved in this process.
Main Methods:
- Induction of chronic systemic P. gingivalis infection in middle-aged mice.
- Analysis of Aβ and inflammatory markers (IL-1β, AβPP770, CatB, Aβ1-42, Aβ3-42) in liver and brain tissues.
- In vitro studies using RAW264.7 cells to assess the effects of blocking Cathepsin B (CatB) and NF-κB.
- Macrophage viability and phagocytic assays using Aβ3-42 and Aβ1-42.
- Examination of Aβ-related markers in gingival tissue macrophages from periodontitis patients.
Main Results:
- P. gingivalis infection led to increased Aβ accumulation in the brain and co-localization with macrophages in the liver.
- Increased expression of IL-1β, AβPP770, CatB, Aβ1-42, and Aβ3-42 was observed in infected mouse livers and periodontitis patient gingival tissues.
- Blocking CatB and NF-κB significantly reduced P. gingivalis-induced inflammatory and Aβ-related gene expression in macrophages.
- Aβ3-42, more so than Aβ1-42, induced macrophage death and impaired phagocytosis.
- Monocytes/macrophages appear to serve as a circulating pool for Aβ in periodontitis patients.
Conclusions:
- Chronic systemic P. gingivalis infection promotes Aβ accumulation in monocytes/macrophages via CatB/NF-κB signaling.
- This mechanism contributes to the Aβ burden in the brain, potentially linking periodontitis to Alzheimer's disease.
- Cathepsin B (CatB) emerges as a potential therapeutic target for mitigating periodontitis-related AD initiation and progression.
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