Posted on 01/15/2010 3:01:11 PM PST by decimon
Studies implicate damage inflicted by amyloid protein as shared disease mechanism
Tampa, FL (Jan. 15, 2010) -- 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. Down syndrome, 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 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 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 birth defect Down syndrome. 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 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 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.” The studies were supported by funds from the USF Health Byrd Alzheimer’s Institute, the Eric Pfeiffer Chair for Research on Alzheimer’s Disease, and the National Institute on Aging, sponsor of the statewide Florida Alzheimer’s Disease Research Center at the University of South Florida. 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).
- USF Health – USF Health (www.health.usf.edu) is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $380.4 million in research grants and contracts last year, the University of South Florida is one of the nation’s top 63 public research universities and one of only 25 public research universities nationwide with very high research activity that is designated as community-engaged by the Carnegie Foundation for the Advancement of Teaching.
Upsetting ping.
Fascinating. Thanks for posting.
“low-density lipoprotein (LDL), the bad cholesterol that causes atherosclerosis, cardiovascular disease and stroke...”
Stopped reading there, it’s a lie.
This sounds a lot like what Duesberg (of Rethinking HIV/AIDS fame) would identify as CANCER. He relates cancer to the creation of cells within our body with the incorrect number of chromosomes. Most of these cells cannot reproduce themselves because of the odd number of chromosomes but some can and those are potentially cancerous. It is an interesting theory.
“Because LDLs transport cholesterol to the arteries and can be retained there by arterial proteoglycans starting the formation of plaques, increased levels are associated with atherosclerosis, and thus heart attack, stroke, and peripheral vascular disease.” - Wikipedia
LDL (Bad) Cholesterol
When too much LDL (bad) cholesterol circulates in the blood, it can slowly build up in the inner walls of the arteries that feed the heart and brain. Together with other substances, it can form plaque, a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis. If a clot forms and blocks a narrowed artery, heart attack or stroke can result.
HDL (good) Cholesterol
About one-fourth to one-third of blood cholesterol is carried by high-density lipoprotein (HDL). HDL cholesterol is known as “good” cholesterol, because high levels of HDL seem to protect against heart attack. Low levels of HDL (less than 40 mg/dL) also increase the risk of heart disease. Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it’s passed from the body. Some experts believe that HDL removes excess cholesterol from arterial plaque, slowing its buildup.
http://www.americanheart.org/presenter.jhtml?identifier=180
“associated” NOT CAUSITIVE.
Try reading “The Great Cholesterol Con” by Dr. Malcolm Kendrick. Or look at his videos on Youtube. It will open your eyes.
Open my eyes to what? That the human body makes cholesterol? That you can't live without it? What?
The “good” cholesterol “bad” cholesterol myth. That most people with heart disease have perfectly acceptable cholesterol levels, that plaque buildup has little to do with animal fats or cholesterol etc etc etc.
Basically most of the crap that the AHA is putting out and that you posted. That’s what.
A conspiracy for everyone and everyone in a conspiracy.
There is nothing new to the claims and counterclaims regarding cholesterol and I’ve no more reason to take the word of this Kendrick than of anyone else.
Decades ago I gave blood to the Red Cross and then received a letter inviting me to participate in a study by, IIRC, the NYU Medical Center and other groups. That was because my triglycerides, lipid thingys and other nasty stuff was sky high. I wasn’t able to participate and never worried about it.
While there are many animal and human studies that DO show a role for LDL and HDL in atherosclerotic disease, it is a very complicated process with many variables (some of which remain undoubtedly unknown). Further, for certain individuals, LDL levels are likely a minor player in overall cardiovascular risk.
One bit of evidence for this is the lack of effect of a powerful statin (Crestor) on cardiovascular mortality in dialysis patients:
Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis
New England Journal of Medicine, Volume 360:1395-1407 April 2, 2009 Number 14
Bengt C. Fellström, M.D., Ph.D., Alan G. Jardine, M.D., Roland E. Schmieder, M.D., Hallvard Holdaas, M.D., Ph.D., Kym Bannister, M.D., Jaap Beutler, M.D., Ph.D., Dong-Wan Chae, M.D., Ph.D., Alejandro Chevaile, M.D., Stuart M. Cobbe, M.D., Carola Grönhagen-Riska, M.D., Ph.D., José J. De Lima, M.D., Ph.D., Robert Lins, M.D., Ph.D., Gert Mayer, M.D., Alan W. McMahon, M.D., Hans-Henrik Parving, M.D., D.M.Sc., Giuseppe Remuzzi, M.D., Ola Samuelsson, M.D., Ph.D., Sandor Sonkodi, M.D., Ph.D., D. Sci., Gultekin Süleymanlar, M.D., Dimitrios Tsakiris, M.D., Ph.D., Vladimir Tesar, M.D., Ph.D., Vasil Todorov, M.D., Ph.D., Andrzej Wiecek, M.D., Ph.D., Rudolf P. Wüthrich, M.D., Mattis Gottlow, M.Sc., Eva Johnsson, M.D., Ph.D., Faiez Zannad, M.D., Ph.D., for the AURORA Study Group
ABSTRACT
Background Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved.
Methods We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events.
Results After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51).
Conclusions In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331 [ClinicalTrials.gov] .)
I didn’t say it was a conspiracy I just said that much of the prevailing wisdom concerning cholesterol and it’s causitive function in heart disease is wrong.
Kendrick states facts that are indisputable, he leaves it to you to make the decison on what to believe.
BTW I have more than a passing interest in this subject as I had a stent put in 2 1/2 years ago. I also had normal triglyceride and cholesterol levels.
Sheesh...you sound like someone who can't take "yes" for an answer. Sorry I bothered...
The conspiracy comment was directed to decimon, I only pinged you out of courtesy as you had entered the discussion.
Sorry for the misunderstanding.
No problem...I get it now. I posted that abstract as support for your position, so your comment seemed strange without the later context you posted.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.