Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H 2 S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy.

Autor: Panagaki T; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Janickova L; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Petrovic D; Leibniz-Institut Für Analytische Wissenschaften-ISAS-E.V., Dortmund, Germany., Zuhra K; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Ditrói T; Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary., Jurányi EP; Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary.; Doctoral School of Semmelweis University, Semmelweis University, Budapest, Hungary., Bremer O; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Ascenção K; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Philipp TM; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Nagy P; Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary.; Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology Research Group, University of Veterinary Medicine, Budapest, Hungary.; Chemistry Institute, University of Debrecen, Debrecen, Hungary., Filipovic MR; Leibniz-Institut Für Analytische Wissenschaften-ISAS-E.V., Dortmund, Germany., Szabo C; Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland. csaba.szabo@unifr.ch.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Oct; Vol. 46 (5), pp. 4275-4314. Date of Electronic Publication: 2024 Apr 01.
DOI: 10.1007/s11357-024-01146-8
Abstrakt: Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H 2 S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H 2 S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H 2 S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.
(© 2024. The Author(s).)
Databáze: MEDLINE
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