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

Abstract

Background: Lipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear. Objective: In this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment. Methods: MG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM). Results: In 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, P.gLPS, 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 APPNL-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. Conclusions: These observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.