SARS-CoV-2 propagation to the TPH2-positive neurons in the ventral tegmental area induces cell death via GSK3β-dependent accumulation of phosphorylated tau.

Autor: Imai M; Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Kawakami F; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Health Administration, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Uematsu T; Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama, Japan., Matsumoto T; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Pathology, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Kawashima R; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Kurosaki Y; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Clinical Chemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Tamaki S; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Maehana S; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan., Ichikawa T; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Hanaki H; Infection Control Research Center, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-Ku, Tokyo, Japan., Kitazato H; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan., Kubo M; Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.; Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Oct 30; Vol. 19 (10), pp. e0312834. Date of Electronic Publication: 2024 Oct 30 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0312834
Abstrakt: COVID-19, an infectious disease caused by SARS-CoV-2, was declared a pandemic by the WHO in 2020. Psychiatric symptoms including sleep disturbance, memory impairment, and depression are associated with SARS-CoV-2 infection. These symptoms are causes long-term mental and physical distress in recovering patients; however, the underlying mechanism is unclear. In this study, we determined the effects of SARS-CoV-2 infection on brain tissue using k18hACE2 mice. Using brain tissue from 18hACE2 mice infected with SARS-CoV-2 through intranasal administration, SARS-CoV-2 spike protein and RNA were analyzed by immunohistochemical staining and in-situ hybridization. Immunohistochemical analysis revealed that Tryptophan hydroxylase 2 (TPH2)-positive cells and SARS-CoV-2 spike protein were co-localized in the ventral tegmental area of SARS-CoV-2-infected mice. We observed decreased TPH2 expression and increased accumulation of phosphorylated tau protein and Phospho-Histone H2A.X (γH2AX) expression in the ventral tegmental region. In addition, activation of glycogen synthase kinase 3β (GSK3β) was induced by SARS-CoV-2 infection. Overall, our results suggest that SARS-CoV-2 infection of TPH2-positive cells in the ventral tegmental area induces neuronal cell death through increased accumulation of phosphorylated tau. Attenuation of the GSK3β pathway and decreased serotonin synthesis through suppression of TPH2 expression may contribute to the development of neurological symptoms.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Imai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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