"Science" blockbuster: the treatment of cognitive impairment in patients with Down syndrome, an important breakthrough!

*For medical professionals only

Down syndrome is one of the most common genetic factors contributing to intellectual disability, with one in every 800 newborns likely to develop Down syndrome [1].

The cause of Down syndrome is that human chromosome 21 has changed from normal two to three, so it is also called trisomy 21
.
Symptoms include significant cognitive impairment, olfactory deficits, low fertility, and more
.

Although more than a century and a half have passed since it was discovered, there are still no effective treatments for Down syndrome so far
.

Recently, a team of researchers led by Vincent Prevot from the University of Lille in France and Nelly Pitteloud from the University of Lausanne in Switzerland published their research in the journal Science
.

They found that progressive neurological symptoms correlated
with levels of gonadotropin-releasing hormone (GnRH) expression in the hypothalamus and outside the hypothalamus.
If GnRH is restored to physiological levels using epigenetic, cytology, chemical genetics, or pharmaceutical interventions, cognitive and olfactory deficits
in Mice with Model Down syndrome can be eliminated.

What's more, they also conducted exploratory clinical studies that found that in adult patients with Down syndrome, treatment with GnRH improves cognitive function
.
Overall, this study provides new ideas and targets for the treatment of Down syndrome
.

Screenshot of the first page of the article

Olfactory defects and fertility disorders in patients with Down syndrome are also typical symptoms
in patients with Kalman syndrome.
Scientists already know that Kalman syndrome is caused by a deficiency in the secretion of the gonadotropin-releasing hormone GnRH[2].

GnRH is a hormone that controls the development of the reproductive system in mammals and is released
in a pulsed manner by specialized neurons in the hypothalamus.
GnRH promotes the release of gonadotropins from the pituitary gland, including follicle-stimulating hormone and luteinizing hormone, thereby regulating reproductive system development
.

Studies have found that Hypothalamic GnRH neurons can project to areas outside the hypothalamus that control intelligence [3-5], suggesting that GnRH may regulate higher brain functions such as learning and memory
in addition to regulating reproductive system development.

During pubertal development, the GnRH system matures and the level of release gradually decreases, while patients with Down syndrome often experience cognitive decline
during adolescence.
So the researchers speculated that cognitive decline in people with Down syndrome may be related to GnRH
.

To test the above conjecture, they fluorescently labeled GnRH in mouse brains and found that by day 90 (adulthood) of the Down syndrome model mice, the expression of GnRH in the brain was significantly lower than in the wild control group
.
Moreover, GnRH neuron projection in the hypothalamus of Mice with Down syndrome mode has almost completely disappeared
at this time.

GnRH expression in the brains of Mice with Down syndrome model was significantly reduced

In fact, as early as 2016, Vincent Prevot's team found that the expression of GnRH is regulated by a molecular switch consisting of the microRNA miR-155 and miR-200 families and their targeted transcription factors Zeb1 and Cebpb, miR-155 and miR-200 inhibiting the expression of Cebpb and Zeb1, respectively, while Zeb1 and Cebpb inhibits the expression of GnRH[6
。

MicroRNA molecular switches regulate GnRH expression

Therefore, they examined the microRNA and gene expression profiles of adult mice and found that compared with the wild type, the expression level of miR-200 family members in the Down syndrome model mice decreased significantly, the expression level of the downstream transcription factors Zeb1 and Cebpb increased, and the expression level of GnRH decreased
.

Thus, in the Down syndrome mode mice, the switch of the molecule that controls GnRH expression is out of balance, resulting in a decrease
in GnRH expression levels.

Imbalances in the expression of switch-related genes regulating GnRH in Mice with Down syndrome mode

So can overexpression of miR-200 save changes in GnRH-related gene expression and cognitive impairment in Down syndrome?

The researchers overexpressed miR-200b, a member of the miR-200 family, in the hypothalamus of Mice with Down syndrome model mice, and found that it could save the expression levels of the GnRH-related genes Zeb1 and Cebpb, increase the number of GnRH neurons, promote synaptic signaling in the hypothalamus, and improve olfactory and cognitive abilities
.

Thus, by regulating the miR-200 molecular switch, the expression level of GnRH can be saved, thereby improving the neurological symptoms
associated with Down syndrome.

Overexpression of miR-200b can save the number of GnRH neurons in Mice with Down syndrome mode

Overexpression of miR-200b can save the sense of smell and cognitive impairment in mice with a pattern of Down syndrome

So can the symptoms of cognitive deficits in Mice with Down syndrome pattern be restored by supplementing GnRH directly?

So the researchers implanted a micropump subcutaneously into the Down syndrome model mice, which can release Lutrelef (a clinically used GnRH peptide for the treatment of infertility caused by insufficient gonadotropin secretion) in pulses, simulating the release of
GnRH in the body under normal physiological conditions.

Through behavioral experiments, the researchers found that both smell and cognitive function in mice implanted with micropumps were significantly restored, suggesting that resuming normal pulsed release of GnRH could improve cognitive symptoms
in mice with Down syndrome patterns.

Further, the researchers also conducted small clinical exploratory studies
in patients with Down syndrome.

They recruited seven adult male patients with Down syndrome and subcutaneously transplanted a LutrePulse micropump at a dose of 75ng per kilogram of body weight per two hours per pulse to simulate the release pattern of GnRH in normal human bodies for a 6-month clinical trial
.

By assessing visuospatial function, executive function, attention, and episodic memory, the researchers found that 6 of the seven patients who received pulsed GnRH showed improved cognitive levels and increased
functional connections in the brain.
Therefore, in patients with human Down syndrome, GnRH pulsed therapy may also be effective
.

Pulsed GnRH therapy improves cognitive performance in patients with Down syndrome

Overall, the researchers found and demonstrated for the first time that expression levels of the gonadotropin-releasing hormone GnRH decreased significantly after puberty, and that GnRH levels were closely related to neurological symptoms in patients with Down syndrome, and that GnRH therapy could serve as a treatment direction
for Down syndrome.

And pulsed GnRH therapy is also safe because it simulates a natural pattern
of hormone release.

At the same time, we also need to note that the sample size of the patients recruited in this study is very small, and large-scale clinical trials are still to be conducted, so it is not yet safe to say that GnRH therapy is clinically effective
.
Moreover, the extent to which this therapy can improve cognitive impairment in Down syndrome requires further clinical research
.

In addition, this study did not do clinical trials in female patients, because the menstrual cycle affects the frequency of GnRH release, and the GnRH release pattern of women is more complex
than that of men.
It is hoped that in the future, with the deepening of research, this therapy can also be applied to women with
Down syndrome.

In fact, this is not the first time that GnRH has other functions besides regulating reproductive development
.
A previous study has shown that levels of GnRH secretion are reduced during aging, thereby promoting aging in the body [7].

Another study found that cognitive decline in Alzheimer's disease is due to rising levels of follicle-stimulating maturation hormone (FSH) during menopause[8], while FSH is directly regulated
by GnRH.

It is expected that through further clinical studies, GnRH therapy will also improve aging and cognitive decline
associated with Alzheimer's disease.

References:

[1].
Manfredi-Lozano M, Leysen V, Adamo M, et al.
GnRH replacement rescues cognition in Down syndrome.
Science.
2022; 377(6610):eabq4515.
doi:10.
1126/science.
abq4515

[2].
Boehm U, Bouloux PM, Dattani MT, et al.
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
Nat Rev Endocrinol.
2015; 11(9):547-564.
doi:10.
1038/nrendo.
2015.
112

[3].
Casoni F, Malone SA, Belle M, et al.
Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains.
Development.
2016; 143(21):3969-3981.
doi:10.
1242/dev.
139444

[4].
Skrapits K, Sárvári M, Farkas I, et al.
The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia.
Elife.
2021; 10:e67714.
Published 2021 Jun 15.
doi:10.
7554/eLife.
67714

[5].
Schang AL, Ngô-Muller V, Bleux C, et al.
GnRH receptor gene expression in the developing rat hippocampus: transcriptional regulation and potential roles in neuronal plasticity.
Endocrinology.
2011; 152(2):568-580.
doi:10.
1210/en.
2010-0840

[6].
Messina A, Langlet F, Chachlaki K, et al.
A microRNA switch regulates the rise in hypothalamic GnRH production before puberty.
Nat Neurosci.
2016; 19(6):835-844.
doi:10.
1038/nn.
4298

[7].
Zhang G, Li J, Purkayastha S, et al.
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.
Nature.
2013; 497(7448):211-216.
doi:10.
1038/nature12143

[8].
Xiong J, Kang SS, Wang Z, et al.
FSH blockade improves cognition in mice with Alzheimer's disease.
Nature.
2022; 603(7901):470-476.
doi:10.
1038/s41586-022-04463-0

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