Mounting evidence has pointed to associations between Alzheimer's disease (AD) and dysbiotic microbiota in the oral cavity and GI tract. However, no studies have compared the role of specific oral and GI-tract pathogens in the development of AD or the roles inflammation severity and sex may play. We compared the effect of chronic exposure to two doses of lipopolysaccharides (LPS) from a periodontal pathogen, Porphyromonas gingivalis, and a GI-tract pathogen, Escherichia coli, on neuroinflammation, cognition, and AD-like pathology. P. gingivalis-LPS, E. coli-LPS, or endotoxin-free PBS was continuously subcutaneously administered to adult male and female C57BL/6 mice for 28 days via osmotic pumps at 250 µg/kg/day (low-dose) or 500 µg/kg/day (high-dose). After 21 days, spatial learning and reference memory were assessed using the Morris Water Maze (MWM) and Y-Maze. After 28 days of LPS treatment, levels of proinflammatory cytokines, TNF-α and IL-β, in serum and brain tissue were measured by ELISA. Markers of AD pathology and inflammation were detected in situ using immunohistochemistry (IHC) in paraffin-embedded brain sections. Western blot (WB) analysis was used to compare the expression of Toll-Like Receptors (TLR) 2 and 4 in brain, bone, liver, and kidney tissues. Sustained exposure to high-dose, but not low-dose, P. gingivalis-LPS or E. coli-LPS significantly impaired cognition in male mice only. P. gingivalis-LPS triggered worse cognitive impairment and neuroinflammation, whereas E. coli-LPS caused more pronounced serum inflammation. IHC analysis revealed that P. gingivalis-LPS-treated male mice had increased amyloid precursor protein and hyperphosphorylated tau protein in both the hippocampus and neocortex, while E. coli-LPS treatment had a less prominent effect. P. gingivalis-LPS also induced a greater degree of astrogliosis. The mechanisms underlying these observations may be related to differential TLR2 and TLR4 expression, as WB analysis showed TLR2 was predominantly expressed in the brain while TLR4 was constitutively expressed in both the brain and peripheral tissues. Overall, P. gingivalis-LPS treatment triggered more prominent neuroinflammation, cognitive impairment, and AD-like pathological brain changes than E. coli-LPS treatment. Moreover, these phenotypes were dose-dependent and sex-dependent. In conclusion, chronic periodontitis may be a significant risk factor for AD, and this relationship warrants further investigation.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48219 |
| Date | 26 February 2024 |
| Creators | Eid, Fady |
| Contributors | Ma, Yun |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-ShareAlike 4.0 International, http://creativecommons.org/licenses/by-nc-sa/4.0/ |
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