NEUROLOGY

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Link Among Alzheimer’s Disease, Down Syndrome and Atherosclerosis

 

We read an article in Scientific American on Trisomy 21 in patients with Alzheimer’s disease (AD). While the reports are a few years old, they are so intriguing that we wanted to share the following from the University of South Florida (14 January 2010).

 

Nearly 20 years ago Huntington Potter proposed the idea that Down syndrome and Alzheimer’s were the same disease. Now, Down syndrome, artery-clogging cardiovascular disease, and possibly even diabetes, appear to share a common disease mechanism with AD. Two papers – one in Molecular Biology of the Cell and the other in PLoS ONE – implicate the Alzheimer’s-associated protein beta amyloid (amyloid protein), which damages the microtubule transport system responsible for moving chromosomes, proteins and other cargo around inside cells. Both studies were done in mice and human cell cultures modeling AD. Together, the laboratory discoveries suggest that protecting the microtubule network from this amyloid damage might be an effective way to prevent or even reverse AD and associated disorders.

 

The first paper, published online (23 Dec. 2009) in Molecular Biology of the Cell (MBC), provides the mechanism behind previous work by Dr. Potter’s laboratory showing that all AD patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is a characteristic shared by all the cells in people with the birth defect Down syndrome. This earlier work demonstrated that AD could be considered a late onset form of Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in AD, including a nerve-killing buildup of sticky amyloid protein clumps. This contributes to accelerated nerve cell loss and dementia. The study reported in MBC showed that the Alzheimer’s-associated amyloid protein is the culprit that 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 and 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 – leading to more accumulation of the “bad“ amyloid protein over a lifetime. According to the authors, AD 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, published (31 Dec. 2009) in the online journal PLoS ONE, describes another consequence of the damaged microtubule network caused by the amyloid protein. As a background, many AD patients also commonly develop vascular diseases and diabetes. Whether this coincidence is bad luck or due to shared disease processes is not yet determined. Research teams have investigated the role that low-density lipoprotein (LDL), the bad cholesterol that causes atherosclerosis, cardiovascular disease and stroke, may play in the development of AD with mixed results. In contrast, the study focused on the amyloid protein’s potential effects on LDL metabolism. The receptor needed to detect and use LDL is among the proteins transported by the microtubules. As previously reported in the MBC paper, the second study found that the amyloid protein inflicts damage to the microtubule network. As a consequence, the receptor needed to pull LDL circulating throughout the bloodstream into the body’s cells has trouble getting to the cell surface to retrieve this bad cholesterol. 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’s. Similarly, 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. As the insulin receptors are needed to get blood sugar inside the cell where it can be used for energy and the nerve cell signaling receptors help promote memory and learning, if these receptors are unable to function properly, it may lead to diabetes and problems with learning and memory.

 

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