Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy

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 p...

Full description

Saved in:
Bibliographic Details
Published in:GeroScience 2024-04, Vol.46 (5), p.4275-4314
Main Authors: Panagaki, Theodora, Janickova, Lucia, Petrovic, Dunja, Zuhra, Karim, Ditrói, Tamás, Jurányi, Eszter P., Bremer, Olivier, Ascenção, Kelly, Philipp, Thilo M., Nagy, Péter, Filipovic, Milos R., Szabo, Csaba
Format: Article
Language:English
Subjects:
Aging
Alzheimer's disease
Amino acids
Animal models
Astrocytes
Autophagy
Biomedical and Life Sciences
Carbohydrate metabolism
Cell Biology
Chromosome 17
Chromosome 21
Cystathionine b-synthase
Down syndrome
Down's syndrome
Endoplasmic reticulum
Geriatrics/Gerontology
Gliosis
Hydrogen sulfide
Immunological memory
Life Sciences
Lipid metabolism
Localization
Molecular Medicine
Neurodegenerative diseases
Neurological complications
Original
Original Article
Pathogenesis
Protein turnover
Spatial discrimination learning
Spatial memory
Synaptosomes
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2509-2723
2509-2715
2509-2723
DOI:10.1007/s11357-024-01146-8