An experimental therapy improves the cognitive abilities of people with Down syndrome

Puberty marks the beginning of cognitive decline in many people with Down syndromeNayeli Cruz

A group of European researchers with a notable Spanish presence has discovered that a fundamental hormone for reproduction also improves the cognition of people with Down syndrome.

After discovering a series of deficiencies in the hormonal mechanism in mice with the same genetic alteration as humans, they injected them with a synthetic version of the hormone.

The rodents improved on various cognitive tests.

Then it was the turn of a small group of humans;

with the same promising result.

The authors, who have published their research in

, and other experts urge caution, as their results will need to be replicated in larger groups.

Gonadotropin-releasing hormone (GnRH) activates a complex mechanism in the brain, releasing two other hormones that act on the testes and ovaries.

Its levels skyrocket at puberty.

Already as adults, the action of GnRH is behind the production of testosterone and sperm in males of all mammals and after the maturation of the ovarian follicle and the production of ovules in females.

In children born with an extra copy of chromosome 21 (the other name for Down syndrome is Trisomy 21), the expression of this hormone is comparable to that of children without this genetic alteration.

But everything changes when puberty arrives.

Thereafter, adults with Down syndrome show a deficit in the release of this hormone, which leads to infertility.

But does GnRH have other functions?

For years it has been suspected that the neurons that release it do something more than regulate the reproductive system, but it was not very well known what.

One of those who has been trying to find out for several years is Vincent Prévot, director of the Laboratory of Development and Plasticity of the Endocrine Brain at the University of Lille (France).

Three things in particular intrigued him, he writes in an email: “One, that Down syndrome patients are able to perceive odors during childhood, but lose it during adolescence.

Two;

Cognitive abilities are fairly comparable between healthy and Down syndrome children, but cognitive decline accelerates after puberty.

And three,

that five genes that code for microRNAs reside on chromosome 21 [these are key RNAs in the control of gene expression] and among them we knew that four were enriched in GnRH neurons”.

Something happens when puberty arrives with this hormone.

“Cognitive abilities are quite comparable between healthy children and those with Down syndrome, but cognitive decline accelerates after puberty”

Vincent Prévot, University of Lille (France)

To clear up so many doubts, they also used mice with Down syndrome, in their case Trisomy 16 (rodents have a slightly different chromosomal configuration than humans).

As in humans, at birth, the pups did not show large differences in GnRH expression when compared to another group of rodents without the extra chromosome.

“But, when we looked at GnRH expression during postnatal development, we found that not only was hormone expression decreased in young adult trisomic mice, but also that in the other mice GnRH neurons sent projections to areas other than the hypothalamus, involved in the control of reproduction, such as brain regions involved in cognition and memory, the cortex and hippocampus, respectively, and that these cortical projections had been lost in trisomic mice,"

The Spanish researcher María Manfredi is the first author of the study, which she carried out during her scholarship stay at the University of Lille.

“Loss of smell with age, infertility, and cognitive decline are all part of Down syndrome,” she says.

"Prévot was convinced of the connection with the hormone GnRH," she adds.

Manfredi and the rest of the team verified in the mice that another population of GnRH neurons different from the one in charge of reproduction carried their connections to other areas of the brain.

Logic led the way: use the hormone, of which there are synthetic versions on the market, to restore its levels in rodents.

They placed a tiny pump that released the molecule in the form of pulses, as the body itself does.

"And we saw that the cognition of mice with Down improved," says the scientist,

“For the first time it is shown that [the hormone GnHR] has projections in the cerebral cortex and the hippocampus, keys for several cognitive abilities”

Manuel Tena-Sempere, researcher at the University of Córdoba

Manuel Tena-Sempere directed Manfredi's thesis at the University of Córdoba and was the one who encouraged her to go with Prévot.

"Yours is a world reference laboratory," he says.

Also co-author of the study, Tena-Sempere points out: “GnRH is a very rare type of specialized neuron, with about 2,000.

It is highly conserved in different species, with the same function in all mammals.

It was suspected that it had some other function.

For the first time it is shown that it has projections in the cerebral cortex and the hippocampus.

By reversing the deficit of this hormone, cognitive improvement occurs.

If this happens in mice, what happens in humans?

It is the last part of the investigation and the shortest, but perhaps the most promising.

Proven the cognitive function of GnRH and the intellectual improvement by balancing it in an animal model, the scientists went further, they wanted to inject the hormone in people with Down syndrome.

This part of the study was led by the neuroendocrine at the University Hospital of Lausanne (Switzerland) Nelly Pitteloud, an expert in human GnRH neurons.

It was not easy for them to recruit a group with trisomy 21. They had to be adults (when the hormonal alteration is greater) and men, since the release in women is more complicated and could affect their menstrual cycle and fertility.

They managed to recruit seven, who received pulses of GnRH every two hours for six months.

“Collectively, they improved their cognition by 30%.”

Nelly Pitteloud, neuroendocrine at the University Hospital of Lausanne (Switzerland)

Six of the seven improved on all of the cognitive tests they were given: visual-spatial function (ability to think in three dimensions), executive function, attention, episodic memory and verbal comprehension.

As for the seventh, "we saw an improvement in certain cognitive abilities mainly driven by the improvement in visual-spatial abilities, executive function and attention", says Pitteloud.

Although it is not easy to express the improvement in figures, the Swiss researcher maintains that “as a whole, they improved their cognition by 30%”.

Hanne Hoffmann is a scientist at Michigan State University (USA).

Unrelated to the study, she has also published in

comment on your results.

In Hoffmann's laboratory they study above all the release of hormones.

Asked about the possible uses of this new therapy, she writes in an email: “GnRH is already used to treat certain types of infertility.

Based on the findings of the study, the pulsatile release of the hormone could be a new treatment for various types of cognitive impairment that may be associated with a functional reduction of GnRH, such as Alzheimer's or Down syndrome."

Since hormone release patterns change with age and "abnormal or decreased release of GnRH is often associated with mental decline with age, its administration could serve to slow the decline," she adds.

But she concludes: “further research is needed to establish the impact of GnRH on cognitive enhancement”

Mara Dierssen is a researcher in the neurobiology of Down syndrome at the Center for Genomic Regulation.

She has had the opportunity to read the research in which she highlights that "the authors convincingly show the involvement of GnRH in the function of brain regions related to learning and memory, such as the hippocampus."

But what she most appreciates about the work is "the imbalance that the authors find in a complex network of microRNAs, which regulates the expression of GnRH and the maturation of GnRH neurons."

She finds it highly relevant that "regulatory elements, such as microRNAs, may play a role in the neuropathology of Down syndrome."

However, Ella Dierssen is very cautious when assessing the results with humans: “The problem is that the clinical study was carried out in a very small group.

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