Leptomeningeal Cells Induce Synaptic Failure via Cathepsin B-mediated IL-1ß Production after Porphyromonas Gingivalis Infection

Abstract Background: Synaptic failure is the earliest sign before Alzheimer’s disease (AD) onset and closely associated with cognitive decline. Clinical studies have shown that periodontitis is positively correlated with both the onset and pathological progression of AD, and preclinical studies have shown that Porphyromonas gingivalis (P. gingivalis), the key pathogen in periodontitis, and its virulence factors induced memory decline in mice. However, the mechanisms underlying the involvement of P. gingivalis in memory decline remain unclear. Methods: We used primary leptomeningeal cells and primary cortical neurons to evaluate the effects of leptomeningeal cells on synaptic generation and plasticity after P. gingivalis infection in vitro. The expression of the related molecules was examined by mRNA in real time and by protein levels using Western blotting. Pharmacological and genetic approaches were used to explore the mechanism underlying the involvement of leptomeningeal cells in synaptic changes after P. gingivalis infection. Results: NLRP3 inflammasome activation was involved in augmenting the IL-1β secretion by primary leptomeningeal cells after P. gingivalis infection, as determined by the knockdown of NLRP3 with siRNA. Cathepsin B (CatB) mediated the activation of both NLRP3 inflammasomes and NF-κB for the production of IL-1β by P. gingivalis-infected primary leptomeningeal cells, as determined by the pharmacologically specific inhibition of CatB. In contrast, P. gingivalis-infected leptomeningeal cells induced an IL-1β-dependent decrease in pre- and post-synaptic molecules in primary cortical neurons, as determined by the pharmacological blockage of the IL-1 receptor. P. gingivalis-infected leptomeningeal cells also induced the IL-1β-dependent suppression of BDNF signaling in cultured N2a neurons, a stable mouse neural cell line. Furthermore, propolis, which is produced by honeybees, suppressed the expression of IL-1β but increased that of BDNF in P. gingivalis-infected leptomeningeal cells. Conclusion: The CatB-mediated IL-1β production was augmented in leptomeningeal cells, resulting in synaptic failure and blockage of BDNF signaling in neurons during P. gingivalis infection. These findings highlight a new mechanism underlying the involvement of periodontitis in AD initiation and suggest that CatB may be an early intervention therapeutic target for delaying the onset of AD during P. gingivalis infection.