Oral Treponema denticola Infection Induces Aβ1-40 and Aβ1-42 Accumulation in the Hippocampus of C57BL/6 Mice

Xinyi Su; Zhiqun Tang; Zhiyue Lu; Yuqiu Liu; Wanzhi He; Jiapei Jiang; Yifan Zhang; Hongkun Wu

doi:10.1007/s12031-021-01827-5

Oral Treponema denticola Infection Induces Aβ_1-40 and Aβ_1-42 Accumulation in the Hippocampus of C57BL/6 Mice

J Mol Neurosci. 2021 Jul;71(7):1506-1514. doi: 10.1007/s12031-021-01827-5. Epub 2021 Mar 24.

Authors

Xinyi Su¹, Zhiqun Tang¹, Zhiyue Lu², Yuqiu Liu¹, Wanzhi He¹, Jiapei Jiang¹, Yifan Zhang¹, Hongkun Wu³

Affiliations

¹ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
² Department of Stomatology Beijing Hospital, Institute of Geriatric Medicine, National Center of Gerontology, Beijing, 100000, China.
³ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China. [email protected].

PMID: 33763842
DOI: 10.1007/s12031-021-01827-5

Abstract

Accumulation of amyloid-β (Aβ) in the brain is a central component of pathology in Alzheimer's disease. A growing volume of evidence demonstrates close associations between periodontal pathogens including Porphyromonas gingivalis (P. gingivalis) and Treponema denticola (T. denticola) and AD. However, the effect and mechanisms of T. denticola on accumulation of Aβ remain to be unclear. In this study, we demonstrated that T. denticola was able to enter the brain and act directly on nerve cells resulting in intra- and extracellular Aβ_1-40 and Aβ_1-42 accumulation in the hippocampus of C57BL/6 mice by selectively activating both β-secretase and γ-secretase. Furthermore, both KMI1303, an inhibitor of β-secretase, as well as DAPT, an inhibitor of γ- secretase, were found to be able to inhibit the effect of T. denticola on Aβ accumulation in N2a neuronal cells. Overall, it is concluded that T. denticola increases the expression of Aβ_1-42 and Aβ_1-40 by its regulation on beta-site amyloid precursor protein cleaving enzyme-1 and presenilin 1.

Keywords: Alzheimer’s disease; Amyloid-β; BACE1; Presenilin 1; Treponema denticola.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors
Amyloid Precursor Protein Secretases / biosynthesis
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / biosynthesis*
Animals
Aorta / microbiology
Aspartic Acid Endopeptidases / biosynthesis
Aspartic Acid Endopeptidases / genetics
Diamines / pharmacology
Enzyme Activation
Hippocampus / metabolism*
Hippocampus / microbiology
Male
Mice
Mice, Inbred C57BL
Mouth / microbiology*
Neurons / metabolism
Neurons / microbiology
Peptide Fragments / biosynthesis*
Porphyromonas gingivalis / pathogenicity
Presenilin-1 / biosynthesis
Presenilin-1 / genetics
Random Allocation
Thiazoles / pharmacology
Treponema denticola / pathogenicity*
Treponemal Infections / metabolism*
Treponemal Infections / pathology
Trigeminal Ganglion / metabolism
Trigeminal Ganglion / microbiology

Substances

24-diamino-5-phenylthiazole
Amyloid beta-Peptides
Diamines
Peptide Fragments
Presenilin-1
Thiazoles
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
presenilin 1, mouse
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Bace1 protein, mouse

Grants and funding

2018SZ0163/Sichuan Province Science and Technology Support Program