Lipopolysaccharides from <i>Porphyromonas gingivalis</i> indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer's disease

BackgroundLipopolysaccharides from <i>Porphyromonas gingivali</i>s (<i>P.g</i>LPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of <i>P.g</i>LPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that <i>P.g</i>LPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with <i>P.g</i>LPS (0.1 μg/mL), soluble Aβ₄₂ (0.1 μM) or AL (combined <i>P.g</i>LPS and soluble Aβ₄₂ at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ₄₂, <i>P.g</i>LPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APP^NL-F/NL-F mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that <i>P.g</i>LPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.