Studies demonstrate link among Alzheimer's disease, Down syndrome and atherosclerosis

January 16, 2010, University of South Florida Health

Nearly 20 years ago Huntington Potter kicked up a storm of controversy with the idea that Down syndrome and Alzheimer's were the same disease. Now the evidence is in: He was right.

And that's not all. , artery-clogging cardiovascular disease, and possibly even diabetes, 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 -- implicate the Alzheimer's-associated protein (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 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 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 21, instead of the usual two. Trisomy 21 is a characteristic shared by all the cells in people with the 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 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 that interferes with 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 of genes. For example, Down syndrome cells contain three copies of the beta amyloid gene on - 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 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 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 (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 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, Dr. Potter said.

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. "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 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."

More information: Journal articles cited:

1. "Alzheimer Ab Peptide Induces Chromosome Mis-segregation and Aneuploidy, including Trisomy 21; Requirement for Tau and APP," Antoneta Granic, Jaya Padmanabhan, Michelle Norden, and Huntington Potter. Molecular Biology of the Cell, Dec. 23, 2009.

2. "LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease," Jose Abisambra, Tina Fiorella, Jaya Padmanabhan, Peter Neame, Inge Wefes, and Huntington Potter, PLoS ONE, Volume 5, Issue 1. (January 2010).

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1 / 5 (1) Jan 16, 2010
If this is true it represents a major advance in medical knowledge. While altered stem cell therapies might, if the problem is caught early enough, reduce some of the symptoms of Downs by reducing the fraction of trisomy 21 cells and so reduce the amyloid, there would still be problems for these patients and for those with small populations of trisomy 21 cells. I find it hard to envision a method of selectively targeting those cells so the beta amyloid would need to be dealt with by another method. But knowing the relationship between the cause and these diseases is an exciting step forward.
1 / 5 (1) Jan 17, 2010
Phenomenal! I can only hope for additional evidence to support the above claims in the article summary of the actual data. I for one hope to see more of this.

I can now see why it is that diabetes sufferers tend to have worse cardiovascular disease at earlier ages than most normal individuals, and why it is that many diabetes sufferers also have forms of dementia onset at earlier times.

The conditions would appear to be interrelated, if the facts hold out. This may hold out hope for potential treatments that tackle the root condition for all of the above conditions.
Jan 17, 2010
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5 / 5 (1) Jan 17, 2010
Perhaps the Gene Silencing descrbed in:http://www.physor...118.html
can be adapted to inhibit one of the chromosome 21 genes in the "three copies of chromosome 21, known as trisomy 21". As noted in the Title of the article, "Silence is Golden", this would close down one of the the offending chromosomes. I have read elsewhere that this "silenced" version of the DNA becomes the duplicated version when new cells are created. This concept would not reverse damage, but would help arrest it.
3.7 / 5 (3) Jan 17, 2010
This does appear to be a rosetta stone moment in medicine, especially as this only-now recognised "suite" of disease comprises probably the largest portion of the fatal diseases in the developed world.
I have no doubt that, as winthrom suggests, that there already exists the knowledge -and probably the tech- to cure the disease, but I think it far more likely that the state of affairs described by sysop is the one likely to prevail.
It's like Chris Rock says- speaking of PHARMA-
"We don't want to CURE it-we just want to make it so that you can LIVE with it..."
Cures don't keep you coming back(paying)for a lifetime. The perfect(and perfectly legal) Pusher/Junkie relationship. A Lifetime of profit for PHARMA.
not rated yet Jan 18, 2010
Finding a link among these diseases hopefully will lead to eliminating the diseases that cripple the lives of both patients and families, emotionally as well as financially.
not rated yet Jan 18, 2010
caliban (and chris rock) you are correct!! to address the idea that "we already have the cure": cannabis has been shown effective in preventing and treating alzheimers; if the connection as related in the article is accurate, then it would stand to reason that cannabis would also be effective in treating artherosclerosis and downs...
not rated yet Jan 19, 2010
If they haven't decided before now they were connected they are wayyyyy behind the times.
Oxidation is the link.
THAT could have been recognized by anyone with half a brain before now.
1 / 5 (1) Jan 22, 2010
You cannot treat Down's Syndrome with cannabis. All you would get is a 'stoned' DS child.

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