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

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.

Periodontitis‐induced neuroinflammation impacts dendritic spine immaturity and cognitive impairment

“…This procedure has the advantage of remaining unbiased by factors such as experimenter manipulation, reflecting an augmentation of existing behavioral activity rather than inducing artificial changes in normal behavioral patterns, and using a high-intensity learning stimulus, which is particularly suitable for older mice (Liu et al, 2012). In this investigation, we uti- the role of P. gingivalis infection in synaptic failure (Huang et al, 2021).…”

“…In this investigation, the conditioned fear test revealed that the CP group demonstrated a reduced memory capacity, aligning with their diminished dendritic spine density. A parallel study indicated that systemic P. gingivalis infection elevated IL‐1 expression and reduced synaptophysin (SYP) expression in the proximal cortex of the leptomeninges in mice, suggesting the role of P. gingivalis infection in synaptic failure (Huang et al, 2021). In yet another study, oral Pg infection was seen to decrease PSD95 and SNAP25 expression in hippocampal and cortex regions in App KI mice (Hao et al, 2022).…”

The oral-brain axis: can periodontal pathogens trigger the onset and progression of Alzheimer’s disease?

“…They discovered that host genes interacting with Pg were significantly enriched in those associated with AD. In addition, mice or rats chronically infected with Pg orally exhibit Pg colonization in the hippocampal and cortical layers, accompanied by classic AD-like pathology such as neuroinflammation, neurodegeneration, Tau phosphorylation, and the formation of both intracellular and extracellular Aβ plaques and NFT ( Wu et al, 2017 ; Ilievski et al, 2018 ; Dominy et al, 2019 ; Díaz-Zúñiga et al, 2020 ; Haditsch et al, 2020 ; Huang et al, 2021 ; Sansores-España L. D. et al, 2021 ; Tang et al, 2021 ; Zeng et al, 2021 ; Hao et al, 2022 ).…”

NLRP3 inflammasome activation in response to metals

“…The NLRP3 inflammasome plays critical roles in various inflammatory disorders, including Alzheimer's disease, diabetes, and other inflammation-related diseases (18)(19)(20). It consists of an N-terminal PYD, a central NOD (also called the NACHT domain), and a C-terminal LRR domain (21).…”