eNews July 01, 2010

Drug normalizes learning in Down syndrome mice

Researchers have long known that people with Alzheimer's disease and those with Down syndrome share a common pathology: the accumulation of β amyloid in the brain. In fact, by age 50 or 60, virtually all people with Down syndrome also develop Alzheimer's disease. Although the accumulation of β amyloid is widely believed to be responsible for the degenerating mental ability and progressive dementia in Alzheimer's, its role in the intellectual disability of young people with Down syndrome is unclear. Recently, however, researchers from The Rockefeller University, New York, found that a drug that reduces β amyloid levels in the brains of individuals with Alzheimer's may also ameliorate cognitive defects in those with Down syndrome (Netzer et al. 2010).

People with Down syndrome have extra APP-encoding gene

Down syndrome results from trisomy of all or part of human chromosome 21. Generally, at least 100 genes, including the ones that encode and up-regulate amyloid precursor protein (APP), are present in triplicate. Cleavage of APP by certain proteases produces several variable length peptides, collectively called β amyloid. People with Down syndrome over-produce β amyloid throughout life, and their β amyloid serum levels are two to three times higher than normal. By age 40, virtually all of them have extensive amyloid plaques in the brain; by age 50 or 60, most develop dementia.

DAPT lowers levels of APP and its metabolites in Ts65Dn mice

The most widely used animal model of Down syndrome is JAX® Mice strain B6EiC3Sn a/A-Ts(1716)65Dn (001924), more popularly known as the Ts65Dn mouse. Partial trisomy of chromosome 16 in this mouse results in triplicate copies of the genes homologous to the most consistently triplicated human chromosome 21 genes, including APP, in Down syndrome. By as early as two to three months, the Ts65Dn mouse exhibits typical, progressive Down syndrome traits, including cognitive deficits. The Rockefeller team found that levels of APP and its protease-cleaved fragments in 4-month-old Ts65Dn mice are more than two times higher than normal, and that β amyloid levels are about one-third higher than normal. Treating the young Ts65Dn mice with DAPT, a drug that inhibits APP proteases, virtually normalizes their β amyloid levels.

DAPT normalizes learning and memory in Ts65Dn mice

The research team wanted to know if DAPT can restore some of the learning and memory deficits of young Ts65Dn mice. Normally, young Ts65Dn mice take significantly more time than controls to learn where either a hidden or visible platform is located in a water maze. However, DAPT-treated Ts65Dn mice learn just as quickly as controls, suggesting that β amyloid affects very complex cognitive and behavioral phenotypes.

The findings by the Rockefeller team added to the growing body of evidence suggesting that cognitive deficits in both Alzheimer's disease and Down syndrome are reversible and that β amyloid-reducing therapies may increase the cognitive abilities of people with Down syndrome.

Reference

Netzer WJ, Powell C, Nong Y, Blundell J, Wong L, Duff K, Flajolet M, Greengard P. 2010. Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One 5:6.