Different Alzheimer's Genes Create Same Problem In Mouse Brain

Researchers showed in genetically engineered mice that a gene linked to a form of Alzheimer's disease that runs in families dramatically increased the speed at which amyloid peptides were made and clumped together to form plaques.

"This gene is not the only force behind accelerated deposition of the plaques, but our findings add to the growing body of evidence supporting the view that this deposition is an early and critical event in Alzheimer's disease," says David Borchelt, Ph.D., an associate professor of pathology.

The findings add to the hope that stopping the early changes with drugs might stop the development of Alzheimer's disease, according to Borchelt.

The study was supported by the National Institutes of Health, the U.S. Public Health Service, and private organizations including the Alzheimer's Association, the Develbliss Fund and the Adler Foundation.

Researchers worked with two mutated human genes that cause AD in patients whose disease runs in their families and starts earlier in life than the more common, non-inherited form of AD.

Amyloid-precursor protein (APP) provides the raw material that forms plaques. The other gene, presenilin 1, is linked to a highly aggressive inheritable form of Alzheimer's, but how it causes the disease is less clear. When the researchers generated mice with a mutated form of APP linked to Alzheimer's disease, the mice developed amyloid plaques at the end of their normal lifespan.

A second group of mice with both mutated APP and presenilin developed numerous amyloid deposits at a much younger age, indicating that presenilin accelerated the rate of plaque formation.

Borchelt says brain levels of amyloid-beta peptide, the substance that clumps to form the plaques, only moderately increased in the second group of mice. However, that increase was enough to halve the time it took for plaques to form.

"A drug that can create a modest reduction in amyloid-beta peptides in the human brain might therefore be able to slow the start of Alzheimer's for many years or even decades," speculates Sangram Sisodia, Ph.D., associate professor of pathology and neuroscience.

Mice for the study were bred by researchers at the National Cancer Institute's Frederick, Md., research center.

Other authors on the paper were Tamara Ratovitski, Judy van Lare, Michael Lee, Vicki Gonzales, Nancy Jenkins, Neal Copeland and Donald Price.