GSK3β is involved in promoting Alzheimer's disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice

In line with the strong association between periodontitis and Alzheimer's disease (AD) clinically, preclinical studies have shown that systemic exposure to Porphyromonas gingivalis (Pg) initiates AD pathologies. However, the involvement of periodontitis in promoting AD pathologies is unclear. In the present study, we provided evidence that chronic systemic exposure to lipopolysaccharide derived from Pg (PgLPS, 1 mg/kg, daily, intraperitoneally) prompted neuroinflammation and tau hyperphosphorylation in 10-month-old of amyloid precursor protein (APP) knock-in mice, a model of AD, carrying the Swedish and Beyreuther/Iberian mutation (APP(NL-F/NL-F)). The learning and memory function were assessed using the passive avoidance test. The production of APP, Amyloid (A)beta(1-42), cytokines, synaptic proteins and the activation of glycogen synthase kinase (GSK)-3 beta as well as phosphorylation of tau were analyzed by immunohistochemistry, Western blotting or an enzyme-linked immunosorbent assay (ELISA) in the cortex of APP(NL-F/NL-F) mice. We found that systemic exposure of PgLPS for three consecutive weeks induced learning and memory deficits with significantly reduced postsynaptic density protein (PSD95). Increased hyperphosphorylation of tau in multiple residues, including Ser202, Thr231 and Ser396, but not the accumulation of A beta 1-42 was detected in the neurons of APP(NL-F/NL-F) mice. Furthermore, PgLPS increased the GSK3 beta activity by reducing its phosphorylation of the serine residue at position 9 (Ser9) and promoted neuroinflammation by increasing the expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF-alpha) while decreasing that of interleukin-10 (IL-10) and transforming growth factor (TGF beta) in the cortex of APPNL-F/NL-F mice. Moreover, the PgLPS-increased GSK3 beta activity was detected in both microglia and neurons, while the PgLPS-increased TNF-alpha expression was mainly detected in the microglia in the cortex of AP(PNL-F/NL-F) mice. In in vitro studies, PgLPS (1 mu g/ml) stimulation increased the mRNA and protein level of TNF-alpha in MG6 microglia, which were significantly inhibited by the GSK3 beta-specific inhibitor TWS119. In contrast, the tau hyperphosphorylation and activation of GSK3 beta in N2a neurons were enhanced after treatment with conditioned medium from PgLPS-stimulated microglia, which was attenuated after pre-treatment with TNF-alpha inhibitor. Taken together, these findings indicate that GSK3 beta is involved in prompting microglia (TNF-alpha)-dependent tau hyperphosphorylation in neurons, resulting in learning and memory deficits in APP(NL-F/NL-F) mice without changes in the A beta expression during chronic systemic exposure to PgLPS. We propose that dampening GSK3 beta activation may help delay the periodontitis-promoted pathological progression of AD.

Automated summary

Chronic systemic exposure to PgLPS derived from Pg induces neuroinflammation and tau hyperphosphorylation in an AD mouse model, leading to learning and memory deficits. This process is mediated by the activation of GSK3 beta and the increase of pro-inflammatory cytokines, suggesting a potential link between periodontitis and the progression of AD pathology.