Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells

Wanyi Huang, Fan Zeng, Yebo Gu, Muzhou Jiang, Xinwen Zhang, Xu Yan, Tomoko Kadowaki, Shinsuke Mizutani, Haruhiko Kashiwazaki, Junjun Ni, Zhou Wu

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Studies have reported that synaptic failure occurs before the Alzheimer's disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation.

OBJECTIVE: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection.

METHODS: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM).

RESULTS: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment.

CONCLUSION: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

Original languageEnglish
JournalJournal of Alzheimer's disease : JAD
DOIs
Publication statusE-pub ahead of print - Jul 27 2021

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