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GEN News Highlights : Jan 18, 2010

Studies Find Link between Alzheimer Disease, Down Syndrome, and Atherosclerosis

Damage inflicted by amyloid protein on the microtubule transport system implicated as shared disease mechanism.

Down syndrome, cardiovascular disease, and possibly even diabetes appear to share a common disease mechanism with Alzheimer disease, according to scientists from the Florida Alzheimer's Disease Research Center and USF Health Byrd Alzheimer's Institute. The discoveries detailed in two separate papers suggest that protecting the microtubule network, responsible for moving chromosomes, proteins, and other cargo inside cells, from amyloid beta damage could be an effective way to prevent or even reverse Alzheimer disease and associated disorders.

Nearly 20 years ago Huntington Potter, Ph.D., senior scientist at Johnnie B. Byrd, Sr. Alzheimer’s Center and Research Institute, put forth the idea that Down syndrome and Alzheimer disease were the same disorder. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer disease, including a nerve-killing buildup of sticky amyloid protein clumps. This contributes to accelerated nerve cell loss and dementia.

Now, researchers led by Antoneta Granic and Dr. Potter demonstrate the mechanism behind the fact that all Alzheimer patients harbor some cells with three copies of chromosome 21 (trisomy 21 is the main characteristic of Down syndrome). The study appears online December 23 in Molecular Biology of the Cell in a paper titled “Alzheimer Ab Peptide Induces Chromosome Mis-segregation and Aneuploidy, including Trisomy 21; Requirement for Tau and APP.”

The findings suggest that the Alzheimer's-associated amyloid protein interferes with the microtubule transport system inside cells. The microtubules are responsible for segregating newly duplicated chromosomes as cells divide. When the microtubule network is disrupted, chromosomes can be incorrectly transported as cells divide. The result is new cells with the wrong number of chromosomes and an abnormal assortment of genes.

For example, Down syndrome cells contain three copies of the beta amyloid gene on chromosome 21. This leads to more accumulation of the amyloid protein over a lifetime, Dr. Potter says. “Alzheimer's disease probably is caused in part from the continuous development of new trisomy 21 nerve cells, which amplify the disease process by producing extra beta amyloid.”

The second paper by lead author Jose Abisambra and colleagues, published December 31 in PLoS ONE, describes another consequence of the damaged microtubule network caused by the amyloid protein. The paper is titled “LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease.”

This second USF team found that as a consequence, the receptor needed to pull LDL cholesterol circulating throughout the bloodstream into the body's cells has trouble getting to the cell surface. This interference with LDL metabolism may allow bad cholesterol to build up in into plaques that choke off blood supply to the brain and heart in people with Alzheimer disease, Dr. Potter explains.

Many Alzheimer disease patients develop vascular diseases and diabetes. Thus, Dr. Potter believes that just like the way movement of the LDL receptor gets disrupted in Alzheimer patients, other key proteins including insulin receptors and receptors for brain signaling molecules are also likely locked inside cells when the transport system is damaged by amyloid or other factors.

“The insulin receptors are needed to get blood sugar inside the cell where it can be used for energy,” says Dr. Potter. “The nerve-cell signaling receptors help promote memory and learning. So, if these receptors are unable to function properly, it may lead to diabetes and problems with learning and memory.”