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Cathepsin B plays a critical role in inducing Alzheimers disease like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice

Cathepsin B plays a critical role in inducing Alzheimers disease like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice
Cathepsin B plays a critical role in inducing Alzheimers disease like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice
A number of clinical and experimental studies have revealed a strong association between periodontitis and accelerated cognitive decline in Alzheimer’s disease (AD); however, the mechanism of the association is unknown. In the present study, we tested the hypothesis that cathepsin (Cat) B plays a critical role in the initiation of neuroinflammation and neural dysfunction following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (PgLPS) in mice (1 mg/kg, daily, intraperitoneally). Young (2 months old) and middle-aged (12 months old) wild-type (WT; C57BL/6N) or CatB-deficient (CatB−/−) mice were exposed to PgLPS daily for 5 consecutive weeks. The learning and memory function were assessed using the passive avoidance test, and the expression of amyloid precursor protein (APP), CatB, TLR2 and IL-1β was analyzed in brain tissues by immunohistochemistry and Western blotting. We found that chronic systemic exposure to PgLPS for five consecutive weeks induced learning and memory deficits with the intracellular accumulation of Aβ in neurons in the middle-aged WT mice, but not in young WT or middle-aged CatB−/− mice. PgLPS significantly increased the expression of CatB in both microglia and neurons in middle-aged WT mice, while increased expression of mature IL-1β and TLR2 was restricted to microglia in the hippocampus of middle-aged WT mice, but not in that of the middle-aged CatB−/− ones. In in vitro studies, PgLPS (1 µg/ml) stimulation upregulated the mean mRNA expression of IL-1β, TLR2 and downregulated the protein levels of IκBα in the cultured MG6 microglia as well as in the primary microglia from WT mice, which were significantly inhibited by the CatB-specific inhibitor CA-074Me as well as by the primary microglia from CatB−/− mice. Furthermore, the mean mRNA expression of APP and CatB were significantly increased in the primary cultured hippocampal neurons after treatment with conditioned medium from PgLPS-treated WT primary microglia, but not after treatment with conditioned medium neutralized with anti-IL-1beta, and not after treatment with conditioned medium from PgLPS-treated CatB−/− primary microglia or with PgLPS directly. Taken together, these findings indicate that chronic systemic exposure to PgLPS induces AD-like phenotypes, including microglia-mediated neuroinflammation, intracellular Aβ accumulation in neurons and impairment of the learning and memory functions in the middle-aged mice in a CatB-dependent manner. We propose that CatB may be a therapeutic target for preventing periodontitis-associated cognitive decline in AD.
0889-1591
350-361
Wu, Zhou
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Ni, Junjun
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Liu, Yicong
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Teeling, Jessica L.
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Takayama, Fumiko
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Collcutt, Alexander
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Ibbett, Paul
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Nakanishi, Hiroshi
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Wu, Zhou
a6e16847-d89a-4b7f-a3a9-4582394de99f
Ni, Junjun
8fd5109a-3c5a-4466-af62-67a66740307f
Liu, Yicong
3c3a7c82-8160-43da-a225-ce8e490bd4bb
Teeling, Jessica L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Takayama, Fumiko
2b105c78-c86b-4bff-940b-94148733ce19
Collcutt, Alexander
dde4c4f9-0a91-4113-aba1-9ca9a9fccc93
Ibbett, Paul
bac07548-e35f-4f01-89c1-71b3404aa4e4
Nakanishi, Hiroshi
c7858f67-0abb-4b8b-a3d4-60ea6cd253e3

Wu, Zhou, Ni, Junjun, Liu, Yicong, Teeling, Jessica L., Takayama, Fumiko, Collcutt, Alexander, Ibbett, Paul and Nakanishi, Hiroshi (2017) Cathepsin B plays a critical role in inducing Alzheimers disease like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain, Behavior and Immunity, 65, 350-361. (doi:10.1016/j.bbi.2017.06.002).

Record type: Article

Abstract

A number of clinical and experimental studies have revealed a strong association between periodontitis and accelerated cognitive decline in Alzheimer’s disease (AD); however, the mechanism of the association is unknown. In the present study, we tested the hypothesis that cathepsin (Cat) B plays a critical role in the initiation of neuroinflammation and neural dysfunction following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (PgLPS) in mice (1 mg/kg, daily, intraperitoneally). Young (2 months old) and middle-aged (12 months old) wild-type (WT; C57BL/6N) or CatB-deficient (CatB−/−) mice were exposed to PgLPS daily for 5 consecutive weeks. The learning and memory function were assessed using the passive avoidance test, and the expression of amyloid precursor protein (APP), CatB, TLR2 and IL-1β was analyzed in brain tissues by immunohistochemistry and Western blotting. We found that chronic systemic exposure to PgLPS for five consecutive weeks induced learning and memory deficits with the intracellular accumulation of Aβ in neurons in the middle-aged WT mice, but not in young WT or middle-aged CatB−/− mice. PgLPS significantly increased the expression of CatB in both microglia and neurons in middle-aged WT mice, while increased expression of mature IL-1β and TLR2 was restricted to microglia in the hippocampus of middle-aged WT mice, but not in that of the middle-aged CatB−/− ones. In in vitro studies, PgLPS (1 µg/ml) stimulation upregulated the mean mRNA expression of IL-1β, TLR2 and downregulated the protein levels of IκBα in the cultured MG6 microglia as well as in the primary microglia from WT mice, which were significantly inhibited by the CatB-specific inhibitor CA-074Me as well as by the primary microglia from CatB−/− mice. Furthermore, the mean mRNA expression of APP and CatB were significantly increased in the primary cultured hippocampal neurons after treatment with conditioned medium from PgLPS-treated WT primary microglia, but not after treatment with conditioned medium neutralized with anti-IL-1beta, and not after treatment with conditioned medium from PgLPS-treated CatB−/− primary microglia or with PgLPS directly. Taken together, these findings indicate that chronic systemic exposure to PgLPS induces AD-like phenotypes, including microglia-mediated neuroinflammation, intracellular Aβ accumulation in neurons and impairment of the learning and memory functions in the middle-aged mice in a CatB-dependent manner. We propose that CatB may be a therapeutic target for preventing periodontitis-associated cognitive decline in AD.

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Accepted/In Press date: 6 June 2017
e-pub ahead of print date: 10 June 2017
Published date: October 2017

Identifiers

Local EPrints ID: 421083
URI: http://eprints.soton.ac.uk/id/eprint/421083
ISSN: 0889-1591
PURE UUID: 92bfefb1-a202-4152-8fbc-9238b9320ae0
ORCID for Jessica L. Teeling: ORCID iD orcid.org/0000-0003-4004-7391

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Date deposited: 22 May 2018 16:30
Last modified: 26 Nov 2021 02:48

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Contributors

Author: Zhou Wu
Author: Junjun Ni
Author: Yicong Liu
Author: Fumiko Takayama
Author: Alexander Collcutt
Author: Paul Ibbett
Author: Hiroshi Nakanishi

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