Grant 15002(HUN-REN–UVMB Laboratory of Redox Biology Research Group (Grant #15002))
European Union’s Horizon 2020(864921)
Subjects:
MEDICAL AND HEALTH SCIENCES
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 (H2S) 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. H2S 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/H2S pathway contributes to the pathogenesis of neurological dysfunction
in DS in the current animal model.
