2004 Investigator-Initiated Research Grant

Every person has 23 pairs of chromosomes. A person with Down syndrome, however, has an extra copy of chromosome 21. A particular segment of this chromosome, when it appears in triplicate rather than duplicate, is believed to be responsible for the features of Down syndrome. This stretch of genetic information is called the Down Syndrome Critical Region (DSCR).

Most individuals with Down syndrome develop the pathological features and symptoms of Alzheimer’s disease in middle age or older adulthood. Scientists suspect that any number of DSCR genes may play a role in causing dementia in people with Down syndrome.

One gene, called DSCR1, appears to be upregulated, or “switched on” more than usual, in the brains of people with Alzheimer’s disease and adults with Down syndrome. Some research suggests that this upregulation may be a protective response to Alzheimer-associated toxic events, as well as a part of the problem when the gene is “on” all the time.

Zhouhua Zhang, Ph.D., and colleagues are investigating DSCR1 and the protein for which the gene provides a “blueprint.” In experiments with cells from autopsied Alzheimer brain tissues and with genetically altered mice that develop an Alzheimer-like disorder, the researchers will assess what mechanisms prompt the upregulation of DSCR1 and how its protein product functions in relation to plaques and tangles, key pathological features of Alzheimer’s disease.

The outcome of this work may help clarify the complexity of molecular interactions in Alzheimer’s disease processes and may suggest new avenues of investigation for drug development.