Alzheimer’s brain protein may provide target for treating mental retardation

The study was led by Paul Greengard, head of the Laboratory of Molecular and Cellular Neuroscience and 2000 Nobel laureate in Physiology or Medicine, and William Netzer, a research associate in Greengard's laboratory. Their research on Down syndrome grew out of the group's interest in Alzheimer's disease, which is the most common form of dementia affecting elderly populations worldwide.

"The buildup of β-amyloid is a central feature in Alzheimer's disease and also in elderly Down syndrome patients who go on to develop Alzheimer's, but it was not known whether β-amyloid contributes to mental retardation in Down syndrome children," says Greengard, Vincent Astor Professor and director of the Fisher Center for Alzheimer's Disease Research at Rockefeller. "Our study suggests that β-amyloid may be a contributing factor in mental retardation, and that gives us hope that it might be possible to improve cognitive abilities in these children."

The accumulation of β-amyloid in the brain is believed to initiate the pathological cascade leading to neuronal dysfunction, cell death and dementia. β-amyloid is derived from a protein called the amyloid precursor protein (APP) as a result of that protein's metabolism by enzymes called secretases, and β-amyloid levels are elevated in Alzheimer's disease patients as well as in both children and adults with Down syndrome. Down syndrome is a complex genetic disorder that's caused by the triplication of more than 100 genes on human chromosome 21, including the gene that encodes APP; the extra APP, scientists believe, results in extra β-amyloid.

Researchers in the Greengard laboratory were aware that nearly all individuals with Down syndrome progress to Alzheimer's dementia by the fifth or sixth decade of life. Though β-amyloid is believed to be responsible for the high prevalence of Alzheimer's in Down syndrome adults, it was not known whether elevated β-amyloid levels influence mental retardation in children with Down syndrome.

The Rockefeller scientists postulated that elevated levels of β-amyloid might influence mental retardation in children with Down syndrome, and that by lowering β-amyloid levels with drugs, cognitive ability in these children might be improved. In other words, mental retardation, which has historically been seen as an irreversible developmental defect, might in fact be treatable with drugs that lower β-amyloid.

"Our study was designed to test our hypothesis that drugs that reduce levels of β-amyloid might improve learning and memory in children with Down syndrome," says Netzer, lead author of the study, which was published in the June issue of PLoS ONE.

Using a mouse model of Down syndrome, the researchers tested a drug-like compound called DAPT, which is a secretase inhibitor known to suppress production of β-amyloid. Mice treated with DAPT not only had a rapid reduction in β-amyloid levels but also a significant improvement in their ability to learn to navigate a water maze and remember where important features were located. The behavior of normal siblings used as a control group was unaffected by DAPT.

Netzer cautions that current compounds used experimentally to lower β-amyloid generally have very toxic side effects. Several years ago, Greengard and his colleagues discovered that the anti-cancer drug Gleevec, used to treat a form of leukemia, lowered β-amyloid without the same side effects as other secretase inhibitors. Although Gleevec does not remain in the brain long enough to treat either Alzheimer's disease or Down syndrome, it may provide a model for developing new anti-amyloid drugs, says Greengard.

Karen Duff, an Alzheimer's researcher from Columbia University Medical Center, also took part in the study; behavioral tests were conducted by Craig Powell's lab at University of Texas Southwestern Medical Center.