Abstract
ABSTRACTThis study explored the origin of age-related granules in the apolipoprotein E gene knockout (ApoE−/−) B6 background mice brains following chronic gingival infection with Porphyromonas gingivalis for 24 weeks. Intracerebral localization of P. gingivalis was detected by fluorescence in situ hybridization (FISH) and its protease by immunohistochemistry. The age-related granules were observed by periodic acid–Schiff (PAS), silver impregnation, and immunostaining. FISH showed intracerebral dissemination of P. gingivalis cells (p = 0.001). PAS and silver impregnation demonstrated the presence of larger inclusions restricted to the CA1, CA2, and dentate gyrus sectors of the hippocampus. A specific monoclonal antibody to bacterial peptidoglycan detected clusters of granules with variable sizes in mice brains infected with P. gingivalis (p = 0.004), and also highlighted areas of diffuse punctate staining equating to physical tissue damage. Mouse immunoglobulin G was observed in the capillaries of the cerebral parenchyma of all P. gingivalis–infected brains (p = 0.001), and on pyramidal neurons in some severely affected mice, compared with the sham-infected mice. Gingipains was also observed in microvessels of the hippocampus in the infected mice. This study supports the possibility of early appearance of age-related granules in ApoE−/− mice following inflammation-mediated tissue injury, accompanied by loss of cerebral blood-brain barrier integrity.
Highlights
The origins of murine age-related granules, first observed in the brains of senescence-accelerated mouse (SAM) models [1], continue to intrigue scientists
The granules within the hippocampus of ApoE−/− mice brain sections demonstrated a degree of argyrophilia, which was difficult to appreciate at low magnification but imperative for showing their location in the CA1 area of the hippocampus (Figure 3(d), box)
The current study was undertaken to investigate whether chronic periodontal bacterial infection could increase circulating inflammatory mediators and could enable bacteria or their structures/antigenic determinants to disseminate into the brain, thereby providing the necessary inflammatory catalyst to trigger the occurrence of periodic acid–Schiff (PAS)-positive, argyrophilic age-related granules
Summary
The origins of murine age-related granules, first observed in the brains of senescence-accelerated mouse (SAM) models [1], continue to intrigue scientists These inclusions appear around 7–8 months of age in SAM mice and have an intimate association with astrocytes [2]. The antioxidant therapy data [19] and the common feature of a defective BBB in humans and ApoE−/− mice [10,11,13] together served as the rationale behind the initiation of this study to explore the role of periodontal infection in augmenting earlier occurrence of age-related granules. This study tested the hypothesis of whether chronic periodontal infection accelerated the appearance of age-related granules in ApoE−/− mice brains
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