Potential Down’s syndrome treatment may improve cognition through epigenetic activity in brain

Down’s syndrome is one of the most common causes of learning disabilities. Caused by the presence of all or part of a third copy of chromosome 21, it is a genetic disorder with no known cure or treatment.

The molecular mechanisms underlying the intellectual disabilities caused by the condition are still unknown. Dyrk1A, a gene located on chromosome 21, has been associated with learning and memory impairments.

Previous studies have shown that Epigallocatechin gallate (EGCG), a polyphenol found in green tea extracts, safely regulates Dyrk1A and can benefit cognition and increase brain functional connectivity in people living with Down’s syndrome.

In a new study published today in Scientific Reports, a journal in the Nature research group, researchers led by Mara Dierssen, principal investigator at the CRG and lead author, describe some of the mechanisms underlying the potential beneficial effects of this treatment.

Using mouse models that replicate Down’s syndrome, the researchers identified five main protein networks that are affected by a triplication of the 21st chromosome, leading to disturbances in protein networks important for neuronal development, chromatin packaging, cell cytoskeleton, enzymatic activity and synaptic activity.

A combined treatment of EGCG and environmental enrichment, which is an experimental method of cognitive stimulation, restored more than 70% of these networks to healthy abundances. The treatment restored protein networks beyond those impaired by the trisomy, which “could be a positive compensatory mechanism that potentiates plasticity related cascades involved in learning and memory”, according to Mara Dierssen.

The researchers also found marked differences in the hippocampus of mouse models with Down’s syndrome, particularly in the activity of histones, proteins that provide structural support to chromosomes and pack them in 3-D space.

“Our findings suggest that the triplication of chromosome 21 could lead to a more repressed chromatin, which in turn might contribute to a reduced expression of memory promoting genes,” says Mara Dierssen. “This would mean that epigenetic regulation is particularly affected in people with Down’s syndrome, whose genome cannot properly express cognitive-related proteins. This is an exciting avenue for new research which we are currently finalising."

“In light of these results, promising combinatorial therapies will boost or prolong current cognitive-enhancement for the treatment of intellectual disabilities,” she concludes.