Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages

Article type: Research Article

Authors: Nie, Ran^{a; 1} | Wu, Zhou^{b; c; 1; *} | Ni, Junjun^{b; *} | Zeng, Fan^b | Yu, Weixian^d | Zhang, Yufeng^e | Kadowaki, Tomoko^f | Kashiwazaki, Haruhiko^g | Teeling, Jessica L.^h | Zhou, Yanmin^{a; *}

Affiliations: [a] Department of Dental Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China | [b] Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan | [c] OBT Research Center, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan | [d] Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, China | [e] Gerontal Department of Stomatology, School and Hospital of Stomatology, Jilin University, Changchun, China | [f] Division of Frontier Life Science, Department of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan | [g] Section of Geriatric Dentistry and Perioperative Medicine in Dentistry, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan | [h] Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom

Correspondence: [*] Correspondence to: Zhou Wu, Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Tel./Fax:+81 92 642 6414; E-mail: zhouw@dent.kyushu-u.ac.jp, Junjun Ni, Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Tel./Fax: +81 92 642 6413; E-mail: nijunjun@dent.kyushu-u.ac.jp and Yanmin Zhou, Department of Dental Implantology, School and Hospital of Stomatology, Jilin University, Changchun 130021, China. Tel./Fax: 043188796025; zhouym62@126.com.

Note: [1] These authors contributed equally to this work.

Abstract: Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770, CatB, Aβ1-42, and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB significantly inhibited the P. gingivalis-induced expression of IL-1β, AβPP770, Aβ1-42, and Aβ3-42 in RAW264.7 cells. Aβ3-42, but not Aβ1-42, induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42. Additionally, the expression of AβPP770, CatB, Aβ1-42, and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κB signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression.

Keywords: Alzheimer’s disease, Cathepsin B, interleukin 1β, monocytes/macrophages, nuclear factor-kappa B, peripheral amyloid-β, Porphyromonas gingivalis infection, systemic inflammation

DOI: 10.3233/JAD-190298

Journal: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 479-494, 2019