Drug Corrects Brain Abnormalities in Mice With Down Syndrome

Down syndrome (DS) results when human babies have three copies of chromosome 21 rather than the normal two copies. However, three copies of pieces of chromosome 21 can also cause DS, and the region of chromosome 21 called the “Down Syndrome Critical Region” can also cause the symptoms of DS. The Down Syndrome Critical Region is located 21q21–21q22.3. Within this region are several genes, that, when present in three copies, seem to be responsible for the symptoms of DS. These genes are APP or amyloid beta4 precursor protein, SOD1 or Superoxide dismutase, DYRK or Tyrosine Phosphorylation-Regulated Kinase 1A, IFNAR or Interferon, Alpha, Beta, and Omega, Receptor, DSCR1 or the Down Syndrome Critical Region Gene 1 (some sort of signaling protein), COL6A1 or Collagen, type I, alpha 1, ETS2 or Avian Erythroblastosis Virus E26 Oncogene Homolog 2, and CRYAz or alpha crystalline (a protein that makes the lens of the eye).

All of these genes have been studied in laboratory animals, and the overproduction of each one of them can produce some of the symptoms of DS. For example, APP overproduction in mice leads to the death of neurons in the brain and inadequate transport of growth factors in the brain (see A.Salehi et al., Neuron, July 6, 2006; and S.G. Dorsey et al., Neuron, July 6, 2006). Also, the overexpression of CRYA1 seems to cause the increased propensity of DS patients to suffer from cataracts. Likewise, overexpression of ETS2 leads to the head and facial abnormalities in mice that are normally seen in human DS patients (Sumarsono SH, et al. (1996). Nature 379 (6565): 534–537).

People can also have only portions of the DS Critical Region triplicated and this leads to graded types of DS that only have some but not all of the symptoms of DS.

Why all this introduction to DS? It is among the most frequent genetic causes of intellectual disability. Therefore, finding a way to improve the cognitive abilities of DS patients is a major goal. T

There is a mouse strain called Ts65Dn mice that recapitulates some major brain structural and behavioral symptoms of DS and these include reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus.

Roger Reeves at Johns Hopkins University has used a drug that activates the hedgehog signaling pathway to reverse the brain deficits of Ts65Dn mice. Yes you read that right.

A single treatment given the newborn mice of the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults.


But wait, there’s more. SAG treatment at birth also improved the hippocampal structure and function. The hippocampus is involved in learning and memory.


SAG treatment resulted in behavioral improvements and normalized performance in a test called the “Morris water maze task for learning and memory. The Morris water maze test essentially takes a mouse from a platform in shallow water and then moves the mouse through the maze and then leave it there. The mouse has to remember how they got there and retrace their steps to get back to the platform before they get too tired from all that swimming. Normally Ts65Dn mice do very poorly at this test. However, after treating newborn Ts65Dn mice with SAG, they improved their ability to find their way back.

SAG treatment also produced other effects in the brain. For example, the ratios of different types of receptors in the brain associated with memory are skewed in Ts65Dn mice, but after treatment with SAG, these ratios became far more normal. Also, the physiology of learning and memory was also more normal in the brains of SAG-treated Ts65Dn mice.

These results are extremely exciting. They confirm an important role for the hedgehog pathway in cerebellar development. Also, they suggest that the development of the cerebellum (a small lobe at the back of the brain involved in coordination and fine motor skills, direct influences the development of the hippocampus. These results also suggest that it might be possible to provide a viable therapeutic intervention to improve cognitive function for DS patients.

This excitement must be tempered. This is an animal model and not a perfect animal model. Also, it is unclear if such a compound will work in humans. Much more work must be done, but this is a fascinating start.

Engineered Neural Stem Cells Restore Cognitive Function

Age-related dementia is a common problem when we age. Neurons in the brain die and neural pathways become corrupted, and we forget things and lose the ability to perform everyday tasks. Can stem cell treatments reverse cognitive decline?

Perhaps they can.  Yun-Bae Kim and Seung U. Kim from the Chungbuk National University College of Veterinary Medicine, in Cheongju, South Korea, and the Division of Neurology at the University of British Columbia Hospital, Vancouver, BC, Canada, have published a couple of papers that use neural stem cells engineered to make the neurotransmitter acetylcholine to treat rodents that have cognitive deficiencies. The results are surprising and hopeful.

Neurotransmitters are small molecules neurons release to talk to each other. Almost a century ago, physicians noticed that patients who took a drug called scopolamine failed to remember certain event after taking the drug. scopolamine is commonly used to treat motion sickness, and if any of you have ever been on board a cruise ship and experienced sea sickness, you were probably prescribed a scopolamine patch. scopolamine works by blocking the neurotransmitter acetylcholine and the fact that scopolamine takers (mind you at much higher concentrations than those used to relieve sea sickness) had memory lapses led neurologists to postulate that acetylcholine plays a role in learning and memory.


The role of acetylcholine in learning and memory has led to the development of treatments for Alzheimer’s disease patients in the form of drugs that increase the effectiveness of endogenous acetylcholine by decreasing its breakdown. These drugs, donepezil (Aricept) and rivastigmine (Exelon), are inhibitors of an enzyme called acetylcholine esterase. This enzyme degrades acetylcholine, thus effectively raising the internal levels of acetylcholine and increasing its activity. These two drugs improve the memory of patients with age-related dementia or the early stages of Alzheimer’s disease (AD).


To that end, Yun-Bae Kim and Seung U. Kim and others have engineered neural stem cells to overproduce and enzyme that synthesizes acetylcholine (choline acetyltransferase). The overproduction of this enzyme by these neural stem cells causes them to overproduce acetylcholine. Implantation of these acetylcholine-overproducing neural stem cells into the brains of laboratory animals that show cognitive declines should provide an excellent indication if such an experiment is feasible in human patients.


In their first experiment, Kim’s research team fed rats a drug that kills off neurons that use acetylcholine. When given to rodents, this drug (ethylcholine mustard aziridinium ion or AF64A) produces memory problems that have some similarities to what is observed in patients with Alzheimer’s disease. Then they transplanted human neural stem cells that made overexpressed acetylcholine into the brains of these memory-challenged rats. Remarkably, the rats with the implanted neural stem cells that overexpressed acetylcholine completely recovered their learning and memory function, and had elevated levels of acetylcholine in their cerebrospinal fluid (CSF). When the brains of these animals were examined in postmortem examinations, they discovered that the human neural stem cells had migrated to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and star-like support cells known as astrocytes. This study shows that brain transplantation of human NSCs that over-expressing acetylcholine improved the complex learning and memory problems in rats with a drug-induced type of Alzheimer’s disease.

In their second paper, the Kim research group did a very similar experiment, but they used a different drug to induce learning and memory problems (kainic acid). The drug was injected directly into the part of the brain known to play a role in learning and memory, the hippocampus. This procedure generated animals with profound learning and memory problems.

The engineered human neural stem cells were injected into the ventricles of the brain, and the cells not only found their way into the brain, but they migrated directly to the damaged area of the brain. The neural stem cells differentiated into neurons and astrocytes and restored, to some degree, the learning and memory defects in these animals.

Taken together, these experiments show that engineered neural stem cells can find their way to the damaged areas of the brain and reconstitute those damaged pathways, at least to some degree. Also, these new neural pathways restore at least some learning and memory defects that result from the death of the acetylcholine-using neurons. These experiments are crying out for more work and confirmation by other groups.

See Park D., et al., Cell Transplant. 2012;21(1):365-71 & Park D., et al., Exp Neurol. 2012; 234(2):521-6