Down syndrome, named for an English doctor and caused by a defect in chromosome 21, occurs approximately once out of every thousand births. It's readily recognizable, producing physical features such as a small chin and a rounded face.
It often leads to cognitive impairment and a range of other medical disorders as well. These include heart disease, epilepsy, and Alzheimer's disease.
As one might expect, Down syndrome greatly reduces life expectancy, although life expectancy has increased in the past few decades. Life expectancy with Down syndrome these days is often limited by the onset of Alzheimer's disease; the protein buildup in the brain often implicated in Alzheimer's disease is even seen in children with Down syndrome.
The exact mechanism of toxicity of these Alzheimer's-implicated proteins is currently under debate; one hypothesis is that they punch holes in nerve cell membranes. Regardless of the correct mechanism of action, the outcome is always fatal.
There is currently no "cure" for Down syndrome. However, treatment of its symptoms with the goal of improving quality of life, especially related to the development of Alzheimer's disease and other life-limiting complications, would be as beneficial as in any other medical condition.
William Netzer (Rockefeller University, United States) and coworkers have contributed to this long-term medical goal. They have rapidly reversed cognitive impairment in a mouse model of Down syndrome.
The mouse model and cognitive testing.
The scientists purchased female mice genetically designed to exhibit Down syndrome. The mice were injected with a synthetic gamma-secretase inhibitor, abbreviated DAPT, receiving roughly 100 milligrams per day.
Gamma-secretase is an enzyme that helps produce Alzheimer's-implicated proteins; inhibiting the enzyme with a drug inhibits the production of these disease-causing proteins. Brain proteins were extracted and detected by standard laboratory protocols.
The scientists tested cognitive abilities in their mice by a water maze experiment. The mice were placed in a water-filled pool (roughly one foot deep), and allowed to swim for one minute until they found a submerged platform.
Once they found the platform, they were left there for 20 seconds prior to removing them. If they did not find the platform after one minute, they were guided to the platform and again left there for 20 seconds prior to removal.
The scientists recorded the time required to find the platform, swimming speed, distance traveled, and the time spent in each of the four sections of the pool. Mice were trained in this procedure four times per day for 11 days, and the resulting data was used to evaluate cognitive function.
Reinstatement of cognitive function.
The scientists confirmed that Alzheimer's-implicated proteins were elevated by a factor of 1.3 to 2.6 in the brains of their Down syndrome mice, depending on the protein. They were all lowered by roughly 50% after treatment with the DAPT drug.
Control mice initially require roughly 30 seconds to find the hidden platform in the water maze, with or without drug treatment. This is similar to Down syndrome mice with drug treatment, but is faster than the over 40 seconds required for Down syndrome mice without drug treatment.
After 11 days of training, Down syndrome mice still require a similar amount of time to find the hidden platform, i.e. no improvement, indicative of cognitive impairment. In contrast, all control mice and the drug-treated Down syndrome mice are able to find the hidden platform after roughly 10 seconds.
This is strongly suggestive of cognitive impairment reversal in Down syndrome mice. Most remarkable was that these results were observed as little as 3 hours after drug treatment.
These results were observed in mice, not humans, and there's no guarantee that humans will respond similarly to treatment with the DAPT drug. Similarly, these experiments do not rule out developmental impairment as another cause of cognitive disability in Down syndrome.
Keeping these cautions in mind, these results do indicate a possible future means of treating Down syndrome. Young Down syndrome patients may be shielded from future cognitive decline by treatment with drugs commonly prescribed to Alzheimer's patients; future research should proceed in this direction.
for more information:
Netzer, W. J, Powell, C., Nong, Y., Blundell, J., Wong, L., Duff, K., Flajolet, M., & Greengard, P. (2010). Lowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model PLoS ONE, 5 (6) DOI: 10.1371/journal.pone.0010943