Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans.
Mol Nutr Food Res
; 58(2): 278-88, 2014 Feb.
Article
in En
| MEDLINE
| ID: mdl-24039182
ABSTRACT
SCOPE Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. METHODS AND RESULTS:
Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study.CONCLUSION:
We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Catechin
/
Protein Serine-Threonine Kinases
/
Down Syndrome
/
Cognition
Type of study:
Clinical_trials
Aspects:
Patient_preference
Limits:
Adolescent
/
Adult
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Mol Nutr Food Res
Journal subject:
CIENCIAS DA NUTRICAO
Year:
2014
Document type:
Article
Affiliation country: