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 (APPNL-F/NL-F). The learning and memory function were assessed using the passive avoidance test. The production of APP, Amyloid (A)β1-42, cytokines, synaptic proteins and the activation of glycogen synthase kinase (GSK)-3β as well as phosphorylation of tau were analyzed by immunohistochemistry, Western blotting or an enzyme-linked immunosorbent assay (ELISA) in the cortex of APPNL-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 Aβ1-42 was detected in the neurons of APPNL-F/NL-F mice. Furthermore, PgLPS increased the GSK3β activity by reducing its phosphorylation of the serine residue at position 9 (Ser9) and promoted neuroinflammation by increasing the expression of interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) while decreasing that of interleukin-10 (IL-10) and transforming growth factor (TGFβ) in the cortex of APPNL-F/NL-F mice. Moreover, the PgLPS-increased GSK3β activity was detected in both microglia and neurons, while the PgLPS-increased TNF-α expression was mainly detected in the microglia in the cortex of APPNL-F/NL-F mice. In in vitro studies, PgLPS (1 µg/ml) stimulation increased the mRNA and protein level of TNF-α in MG6 microglia, which were significantly inhibited by the GSK3β-specific inhibitor TWS119. In contrast, the tau hyperphosphorylation and activation of GSK3β in N2a neurons were enhanced after treatment with conditioned medium from PgLPS-stimulated microglia, which was attenuated after pre-treatment with TNF-α inhibitor. Taken together, these findings indicate that GSK3β is involved in prompting microglia (TNF-α)-dependent tau hyperphosphorylation in neurons, resulting in learning and memory deficits in APPNL-F/NL-F mice without changes in the Aβ expression during chronic systemic exposure to PgLPS. We propose that dampening GSK3β activation may help delay the periodontitis-promoted pathological progression of AD.

Objectives: Prolonged grief disorder (PGD) is prevalent and associated with increased psychiatric-comorbidities and suicidality. This study investigates the effect of Brief Reminder-Focused Positive Psychiatry and Suicide-Prevention (RFPP-S) in youth with COVID-19 related PTSD and PGD. Methods: 41 consecutive adolescents (ages 14 ± 4 years, 60% female) with COVID-19 related PTSD and PGD with SI received RFPP-S at the psychiatry-emergency-room (PER). RFPP-S consisted of 10-minute behavioral-modules, in 2 consecutive-days, on self-compassion, engagement, resilience, gratitude for traumatic/loss reminders with emotion regulation, distress tolerance, and safety planning skills. Results: The prevalence of youth PER visits was 61% higher in 2020. That constitutes 40% with COVID-19 related PTSD, with the presence of grief symptoms in over 90%. There was a significant reduction in Columbia suicide severity rate scale (C-SSRS), persistent complex bereavement disorder (PCBD) checklist, and PTSD reaction index in response to RFPP-S. Furthermore, RFPP-S is associated with an increase in wellbeing, resilience, parent-child interaction, school performance, post-discharge follow-up, and no PER visit/psychiatric-hospitalization 4-week after discharge. Conclusions: RFPP-S is associated with reducing PTSD and grief symptoms, acute psychiatric stabilization, parent-child interactions, and favorable outcome in youth with COVID-19 related PTSD and PGD.