老年痴呆症、唐氏症、动脉硬化病理可能相同

Nearly 20 years ago Huntington Potter kicked up a storm of controversy争论，辩论 with the idea that Down syndrome唐氏症 and Alzheimer's were the same disease. Now the evidence is in: He was right. And that's not all. Down syndrome, artery-clogging动脉堵塞 cardiovascular disease心血管疾病, and possibly even diabetes糖尿病, appear to share a common disease mechanism with Alzheimer's disease,

Dr. Potter and colleagues at the Florida Alzheimer's Disease Research Center, USF Health Byrd Alzheimer's Institute, recently reported.

The researchers' two papers – one in Molecular Biology of the Cell and the other in PLoS ONE -- implicate暗示，牵连 the Alzheimer's-associated protein beta amyloid淀粉质食物 (amyloid protein), which damages the microtubule微管 transport system responsible for moving chromosomes染色体, proteins and other cargo around inside cells. Both studies were done in mice and humans cell cultures modeling Alzheimer's disease. Together, the laboratory discoveries suggest that protecting the microtubule network from this amyloid damage might be an effective way to prevent or even reverse颠倒，倒转 Alzheimer's disease and associated disorders.

The first paper, by Antoneta Granic and colleagues published online Dec. 23 in Molecular Biology of the Cell, provides the mechanism behind previous work by Dr. Potter's laboratory showing that all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy三染色细胞体 21, instead of the usual two. Trisomy 21 is a characteristic shared by all the cells in people with the birth defect Down syndrome as well. This earlier work demonstrated that Alzheimer's disease 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病理学 seen in Alzheimer's disease, including a nerve-killing buildup of sticky amyloid protein clumps. This contributes to accelerated nerve cell loss and dementia.

With the study reported in MBC, Dr. Potter and his colleagues now show that the Alzheimer's-associated amyloid protein is the culprit犯人，罪犯 that interferes with干扰，妨碍 the microtubule transport system inside cells. The microtubules are responsible for segregating newly duplicated chromosomes as cells divide.

"Beta amyloid basically creates potholes in the protein highways that move cargo, including chromosomes, around inside cells," said Dr. Potter, who holds the Eric Pfeiffer Endowed Chair for Research on Alzheimer's Disease.

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分类，混合物 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, Dr. Potter says. "Alzheimer's disease probably is caused in part from the continuous development of new trisomy 21 nerve cells, which amplify放大，增强 the disease process by producing extra beta amyloid."

The second paper by lead author Jose Abisambra and colleagues, published Dec. 31 in the online journal PLoS ONE, describes another consequence of the damaged microtubule network caused by the amyloid protein.

Many Alzheimer's disease patients also commonly develop vascular血管的 diseases and diabetes. Whether this coincidence is bad luck or due to shared disease processes is intensely debated. Research teams have investigated the role that low-density lipoprotein脂蛋白 (LDL), the bad cholesterol that causes atherosclerosis, cardiovascular disease and stroke, may play in the development of Alzheimer's with mixed results. However, the USF group 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 by their colleagues in the MBC paper, the second USF team found that the amyloid protein inflicts给予，造成 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重新得到，恢复 this bad cholesterol. This interference with LDL metabolism may allow bad cholesterol to build up in into plaques版块，瓷片 that choke off阻止 blood supply to the brain and heart in people with Alzheimer's, Dr. Potter said.

Similarly, other key proteins – including insulin胰岛素 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. The nerve cell signaling receptors help promote memory and learning," Dr. Potter said. "So, if these receptors are unable to function properly, it may lead to diabetes and problems with learning and memory."

"We're beginning to understand how conditions like cardiovascular disease and diabetes may manifest证明，表明 some of the same underlying disease processes as Alzheimer's disease," he said, "rather than being independent diseases that just happen to develop in the same patient."