Can the cognitive impairments of Down’s syndrome be prevented? A decade ago, no one even asked this question. Cognitive difficulties were assumed to be an inevitable consequence of carrying an extra copy of chromosome 21. With the advent of mouse models, however, researchers have begun to dissect what goes wrong in the brain during development and address how to correct it. At a symposium at the Society for Neuroscience annual meeting held in Chicago October 17-21, speakers made the case that early postnatal or even prenatal treatment can restore normal brain structure and size and prevent cognitive defects in mice that model the disorder. With additional research, some of these approaches might be ready for testing in human clinical trials within three to five years, co-chairperson Diana Bianchi of Tufts Medical Center, Boston, wrote to Alzforum. Chairperson Renata Bartesaghi of the University of Bologna, Italy, emphasized that for the first time, researchers hold hope that they may be able to help people with Down’s syndrome to live more independently.

“This is a very exciting time in Down’s syndrome research,” said Ted Brown, who heads the Medical Genetics Laboratory at the Institute for Basic Research, Albany, New York. Michael Harpold of the LuMind Foundation, a non-profit in Marlborough, Massachusetts, that supports Down’s syndrome research, said he was encouraged by the progress in this area. He noted that several drugs targeting cognition are already in clinical trials for children and adults with Down’s syndrome (for review, see Gardiner, 2014). Prenatal treatments, however, would represent a sea change in how researchers approach the condition.

Restored Neurogenesis. Adult mice that model Down’s syndrome (middle) have fewer granule cells (purple) compared to controls (left); prenatal treatment with fluoxetine (right) restores cell number. [Courtesy of Renata Bartesaghi.]

Down’s syndrome is fairly common, occurring in about one in 700 live births. People who are affected carry one extra copy each of about 360 genes found on chromosome 21, disrupting numerous processes including the cardiac, digestive, and motor systems. The most notable feature of Down’s, however, is cognitive impairment. The brain develops abnormally in utero. Fewer neurons are born, and they segregate to the wrong cortical layers. By 15 weeks of pregnancy, brains of DS children are significantly smaller than those of other babies, with a shrunken cortex and cerebellar volume about 80 percent of normal.

The first useful mouse model of Down’s syndrome, Ts65Dn, was developed in 1993 (see Davisson et al., 1993). It carries extra copies of many of the genes on human chromosome 21, though it is not a perfect genetic match for the human condition. The mice share many physical and behavioral features of DS, and mirror the defects in early brain development (see Feb 2000 news; Tyler and Haydar, 2013). Speakers agreed that this model, and others that followed, revolutionized DS research. “Ts65Dn broke open the door,” said Tarik Haydar from Boston University.

Surprisingly, research in this mouse suggested that its complex learning and memory defects could be corrected if relatively simple treatments, such as neurotrophic factors or activators of sonic hedgehog, a crucial developmental signaling molecule, were given early enough (see Roper et al., 2006; Toso et al., 2008). At SfN, Bartesaghi presented another such approach. She noted that the serotonin signaling system is suppressed in DS brains from the embryonic stage, and wondered if selective serotonin reuptake inhibitors might normalize it. She treated newborn Ts65Dn mice with 5-10 mg/kg fluoxetine (Prozac) for two weeks, which is roughly equivalent to doses people take for depression. Treated mice mustered as many neurons and synapses as control mice, and had normal thickness of the granule cell layer of the cerebellum (see image above). At six weeks old they learned as well as wild-type mice in fear conditioning tests, Bartesaghi reported. In addition, neurons had wild-type levels of the β-CTF fragment of APP, and showed no signs of the swollen endosomes that accumulate in AD brains and may be a precursor to AD-like degeneration (see Bianchi et al., 2010Stagni et al., 2015; May 2011 news). The data suggest that the early treatment not only normalized serotonin transmission, but neurodevelopment and APP processing as well.

Next, Bartesaghi and colleagues treated pregnant Ts65Dn mice with 10 mg/kg fluoxetine, starting 10 days after conception and ending at birth. The authors did not measure fluoxetine levels in the pups’ brains, however, as with postnatal treatment, the offspring had normal cerebellar thickness and neuron numbers at birth and six weeks of age, based on counts from numerous brain regions. They also behaved like wild-type mice at six weeks old, performing normally in fear conditioning tests and displaying none of the hyperactivity that characterizes the Ts65Dn mice (see Guidi et al., 2014). 

The data were well-received, with one scientist saying he was “blown away” by the findings. However, the results are still preliminary. Bartesaghi noted she has not yet conducted a thorough safety study, including assaying for the cardiac problems that can occur with SSRI use, nor has she looked for a dose response or tested the drug in other mouse models. In answer to an audience question, Bartesaghi said it is not yet clear whether there is a difference between treating prenatally or early postnatally, although she suggested that prenatal treatment is likely to have a more widespread effect on the brain.

Could prenatal treatments from mice be applied to people? Doctors would first have to diagnose DS early enough. Bianchi pointed out that new cell-free DNA screening tests, available since 2011, can detect DS at 11 weeks gestation with more than 99 percent accuracy. Though results still need to be confirmed with invasive testing, this could provide a window for early intervention, she noted. However, drugs for prenatal treatment would need to have an excellent safety profile, and be able to cross the placenta as well as the blood-brain barrier.

Bianchi outlined an approach to finding new drug candidates. She analyzed gene expression using RNA from the amniotic fluid of DS babies, and saw from multiple samples a consistent pattern in 15- to 16-week-old fetuses. Comparison of the gene-expression pattern to that of normal babies revealed that oxidative stress pathways were particularly disrupted (see Slonim et al., 2009). This matches data from studies of Ts1Cje mice that model the disease (see Guedj et al., 2015). Bianchi then looked for drugs that would normalize expression. She used the Connectivity Map created by the Broad Institute of MIT and Harvard, which profiles 1,309 FDA-approved drugs by microarray analysis to show how each one affects gene expression. From this list, Bianchi and colleagues identified 47 compounds that targeted the major pathways, including oxidative stress, ion transport, and G protein signaling, which were disrupted in both people with DS and Ts1Cje mice. The researchers then used analytical software to rank these drugs by their expected ability to correct gene expression.

One of the top candidates was apigenin, an antioxidant found in leafy green vegetables, citrus fruits, and chamomile tea. Apigenin is a dietary supplement under investigation as an anti-cancer agent. It purportedly promotes neurogenesis (see Taupin, 2009). Bianchi and colleagues tested the compound on cultured DS cells and found it prevented the “unspooling” of DNA. This is when the nucleic acid unwinds from its dense chromatin packaging—a known marker of oxidative stress. The researchers then fed 200 mg/kg apigenin daily to pregnant Ts1Cje mice. During the first few weeks after birth, the offspring remembered better and reached developmental milestones sooner than those born of untreated controls. Apigenin did not improve all DS symptoms, however, as motor skills remained poor. In future work, the researchers will test apigenin in other mouse models, and will also examine whether combination drug treatment produces better results, Bianchi said.

Other researchers are taking a different approach to normalizing brain development. Previously, researchers identified excessive synaptic inhibition as one of the primary problems in mouse models of DS (see Siarey et al., 1997; Kleschevnikov et al., 2004; Mar 2015 news). At SfN, Jean-Maurice Delabar of Paris Diderot University, France, noted that the kinase DYRK1A helps control the balance between excitation and inhibition in the brain (see Souchet et al., 2014). People with Down’s syndrome, as well as Ts65Dn mice, carry an extra copy of this gene. Moreover, transgenic mice that overexpress DYRK1A generate excessive inhibitory interneurons and have disorganized brain layers, fewer neurons, and connectivity problems (see Najas et al., 2015). The transgenics demonstrate that this single gene can recapitulate many of the problems in DS brains. The kinase appears to affect other aspects of Down’s syndrome as well, such as skeletal abnormalities (see, e.g., Blazek et al., 2015). The data suggest the kinase might be a promising target for restoring healthy brain function in Down’s syndrome, Delabar said.

Delabar tested this approach by treating adult Ts65Dn mice for one month with epigallocatechin gallate (EGCG), a polyphenol found in green tea. EGCG inhibits DYRK1A (see Bain et al., 2003Guedj et al., 2009). Hippocampal slices from treated animals had better LTP and the mice had sharper memories, though they still sported more inhibitory interneurons than usual, Delabar reported. He is now testing EGCG in pregnant Ts65Dn mice. By contrast with postnatal treatment, preliminary results suggest that prenatal treatment lowered the number of inhibitory interneurons in the offspring to normal levels, he said. In a pilot clinical study, adults with Down’s syndrome who took EGCG scored better on memory tests (see De La Torre et al., 2014). 

Mara Dierssen of the Center for Genomic Regulation, Barcelona, who collaborated with Delabar on several studies, made a case for combining EGCG treatment with cognitive stimulation. When mice are housed in cages with toys, they perform better on learning and memory tests. Dierssen previously found that such environmental enrichment can normalize DYRK1A activity in mice overexpressing the gene, and hypothesized that it might have synergistic effects with EGCG (see Pons-Espinal et al., 2013). She found that the two treatments together were more effective than either alone at boosting memory in six- to seven-month-old Ts65Dn mice. The combination treatment also preserved cholinergic neurons, but the single interventions did not. 

In children with DS, computerized cognitive training has been used to improve memory (see Bennett et al., 2013). Dierssen tested a combination of pharmacological and cognitive treatments in a Phase 2 clinical trial of 31 teens and young adults with Down’s syndrome. Participants took either EGCG supplements or placebo for three months, and some in each group also took part in computerized cognitive training. As with the mice, those who received both interventions demonstrated more improvement on memory tests than those who had only one, Dierssen reported. Moreover, functional MRI revealed that the regions of their brains worked together more smoothly, suggesting better connectivity after treatment. Improvements lasted at least three months after treatment stopped. DYRK1A may prime cells so that the effects of environmental enrichment are more stable, Dierssen suggested.

Dierssen noted that DYRK1A also affects amyloidogenesis, and so could be targeted in adults with DS to try to slow amyloid-β accumulation (see Coutadeur et al., 2015Naert et al., 2015). Because people with DS carry three copies of APP, they develop amyloid pathology by their 40s (see Jun 2011 news). Intriguingly, EGCG has been found to block amyloid formation and has been tested, but never developed, as an Alzheimer’s treatment (see Oct 2005 conference newsMay 2008 news). 

Carmen Martinez-Cué of the University of Cantabria, Santander, Spain, focused on slowing AD pathology in her talk. She is trying several strategies in DS models. In one approach, she treated adult Ts65Dn mice with melatonin for seven months. Melatonin regulates circadian rhythms, but also suppresses inflammation, oxidative stress, and APP while boosting neurogenesis, suggesting it might help protect aging brains. Treatment lowered lipid peroxidation and protein damage in hippocampus, Martínez-Cué reported. In addition, treated animals had better cognition along with improved neurogenesis and LTP in the hippocampus, though not to the level of that in normal controls (see Corrales et al., 2013; Corrales et al., 2014). In a second strategy, Martinez-Cué developed a neutralizing antibody to the proinflammatory cytokine IL-17. She administered this antibody to Ts65Dn mice from five to 12 of months of age to try to quiet neuroinflammation. Treated mice displayed more neurogenesis and less Aβ. They performed better in a water maze than untreated littermates, but again not to control levels.

In the end, many different approaches may be needed to combat all the symptoms of Down’s syndrome, Bianchi told the crowd. These problems span the gamut from early brain abnormalities to muscle weakness to neurodegeneration, and may each present different windows for intervention. Randall Roper of Indiana University-Purdue University, Indianapolis, wrote to Alzforum, “The big hurdle to me is to show how and where potential therapies are working at the cellular and molecular level … It is important to have sufficient funding to continue necessary basic science research before large-scale clinical trials begin.” Research into these areas is accelerating. Bianchi noted that scientists founded the non-profit Trisomy 21 Research Society in 2014, and this group held its first meeting June 4-7 in Paris. In advance of the SfN symposium, the presenters wrote up a preview of their talks, which appeared in the October 14 Journal of Neuroscience.—Madolyn Bowman Rogers


  1. It’s amazing to me that we are now talking about treating cognitive disabilities associated with Down’s syndrome. The data presented at SfN give hope that there are a number of potential therapies that might treat Down’s syndrome phenotypes, as well as several time points when intervention might be effective. Animal models have provided, and will continue to provide, a wealth of information to help us understand how particular therapies work. To me, the big hurdle is to show how and where potential therapies are working at the cellular and molecular levels. I do not believe one therapy will be able to overcome all of the cognitive phenotypes. It will be important to test the impact of individual components of combination treatments to find their effects. It is also important to have sufficient funding to continue the necessary basic science research. Then well-designed clinical trials will be important to understand the impact that potential treatments might have on individuals with Down’s syndrome.

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News Citations

  1. Down's Syndrome Mouse Model Shows Facial Deformities
  2. Lysosomal Block Clogs Transport, Swells Neurites
  3. About-Turn—In Mouse Model of Down’s Syndrome, Inhibitory Neurotransmitter Excites
  4. Research Brief: Imaging Shows AD Pathology in Down’s Syndrome Brains
  5. We Are What We Consume? Foods, Drugs Affect Amyloid, AD
  6. A Fortune in Tea Leaves—Extract Blocks Amyloid Formation

Paper Citations

  1. . Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. Drug Des Devel Ther. 2015;9:103-25. Epub 2014 Dec 17 PubMed.
  2. . Segmental trisomy as a mouse model for Down syndrome. Prog Clin Biol Res. 1993;384:117-33. PubMed.
  3. . Multiplex genetic fate mapping reveals a novel route of neocortical neurogenesis, which is altered in the Ts65Dn mouse model of Down syndrome. J Neurosci. 2013 Mar 20;33(12):5106-19. PubMed.
  4. . Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1452-6. PubMed.
  5. . Prevention of developmental delays in a Down syndrome mouse model. Obstet Gynecol. 2008 Dec;112(6):1242-51. PubMed.
  6. . Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. J Neurosci. 2010 Jun 30;30(26):8769-79. PubMed.
  7. . Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice. Neurobiol Dis. 2015 Feb;74:204-18. Epub 2014 Dec 10 PubMed.
  8. . Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model. Brain. 2014 Feb;137(Pt 2):380-401. Epub 2013 Dec 12 PubMed.
  9. . Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9425-9. PubMed.
  10. . The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome. Am J Med Genet A. 2015 Sep;167A(9):1993-2008. Epub 2015 May 14 PubMed.
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  12. . Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down Syndrome. Neuropharmacology. 1997 Nov-Dec;36(11-12):1549-54. PubMed.
  13. . Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci. 2004 Sep 15;24(37):8153-60. PubMed.
  14. . Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. Neurobiol Dis. 2014 Sep;69:65-75. Epub 2014 May 4 PubMed.
  15. . DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome. EBioMedicine. 2015 Feb;2(2):120-34. Epub 2015 Jan 17 PubMed.
  16. . Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a. Hum Mol Genet. 2015 Oct 15;24(20):5687-96. Epub 2015 Jul 23 PubMed.
  17. . The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. PubMed.
  18. . Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One. 2009;4(2):e4606. Epub 2009 Feb 26 PubMed.
  19. . Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014 Feb;58(2):278-88. Epub 2013 Sep 14 PubMed.
  20. . Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A. Neurobiol Dis. 2013 Dec;60:18-31. Epub 2013 Aug 20 PubMed.
  21. . Computerized memory training leads to sustained improvement in visuospatial short-term memory skills in children with Down syndrome. Am J Intellect Dev Disabil. 2013 May;118(3):179-92. PubMed.
  22. . A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro. J Neurochem. 2015 May;133(3):440-51. Epub 2015 Jan 26 PubMed.
  23. . Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice. Eur Neuropsychopharmacol. 2015 Nov;25(11):2170-82. Epub 2015 Apr 10 PubMed.
  24. . Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome. J Pineal Res. 2013 Apr;54(3):346-58. Epub 2013 Jan 25 PubMed.
  25. . Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model of Down syndrome. J Pineal Res. 2014 Jan;56(1):51-61. Epub 2013 Nov 25 PubMed.

External Citations

  1. Connectivity Map
  2. Phase 2 clinical trial 
  3. Trisomy 21 Research Society

Further Reading


  1. . Prenatal treatment of Down syndrome: a reality?. Curr Opin Obstet Gynecol. 2014 Apr;26(2):92-103. PubMed.

Primary Papers

  1. . New Perspectives for the Rescue of Cognitive Disability in Down Syndrome. J Neurosci. 2015 Oct 14;35(41):13843-52. PubMed.