A study of 209 families with at least two siblings with Alzheimer's and one unaffected sibling showed that those with this genetic variation are less likely to have the disease, researchers say in Neurobiology of Aging. An estimated 25 percent of the population has the XmnI polymorphism.
The study, available online but not yet scheduled for print, also showed that beta amyloid peptide, a major culprit in Alzheimer's, has an affinity for adult hemoglobin, says Dr. William D. Hill, neuroscientist at the Medical College of Georgia and Veterans Affairs Medical Center in Augusta and a corresponding author.
The hemoglobin attraction was discovered by using phage display technology to screen thousands of molecules in the human brain to find those that interact with beta amyloid peptide. This approach uses a virus to infect a bacterium so the bacterium will copy the virus.
The result looks like a microscopic cigar with the proteins of interest as whiskers on one end, says Dr. Hill. In this case, a library of brain molecules was inserted into the virus' whiskers to find proteins that would stick to beta amyloid.
Hemoglobin, found in red blood cells and responsible for carrying oxygen in the body, was among those that stuck.
Surprised that hemoglobin was even present, Dr. Hill suspected it was an artifact of preparing brain tissue for the library. But once he saw the attraction, he could not ignore it.
His lab actually first found an attraction for fetal hemoglobin, another surprise since most adults have little of this substance that snatches oxygen from the placenta and holds onto it tightly for the fetus. Looking further, his lab found adult hemoglobin was binding as well, so Dr. Hill and MCG hemoglobin experts Drs. Abdullah and Ferdane Kutlar decided to look at the XmnI polymorphism, which can significantly increase fetal hemoglobin expression in adults.
They turned to colleagues at the University of Alabama at Birmingham, one of three sites that contributed families to the National Institute of Mental Health Alzheimer's databank.
At the UAB databank, headed by Dr. Rodney C.P. Go, researchers found more surprises. "We wanted to look at people who had Alzheimer's and family members who don't to see who expressed the polymorphism the most," says Dr. Hill. They expected it would be the Alzheimer's patients and found just the opposite.
In what they suspect to be a horrific vicious cycle, beta amyloid could injure red blood cells, allowing more of them than usual to break open and spill their contents, including oxygen-carrying hemoglobin, into the bloodstream. Free hemoglobin is toxic; it can easily lose its iron group, causing cell-damaging oxidative stress. Now it appears freed hemoglobin may also bind to beta amyloid, which may enhance that protein's ability to wreak havoc in the brain.
Red blood cells break down every day and the body has molecules that bind free hemoglobin and iron and take them to the liver for elimination. "Part of our hypothesis is that it may be free-radical injury of our red blood cells by the beta amyloid that releases excessive hemoglobin which overwhelms our body's natural system for protecting us from free hemoglobin," Dr. Hill says.
Work in the late 1990s showed fragments of beta amyloid could actually attack red blood cell membranes and cause them to destruct, says Dr. Hill. "And, there is some evidence that red blood cells of Alzheimer's patients have been damaged so we think red blood cells are more fragile in some Alzheimer's patients allowing them to be more likely to break open.
Although the XmnI polymorphism's protection mechanism is not clear, the researchers found in certain circumstances, adult hemoglobin bound better to beta amyloid, so if there are higher levels of fetal hemoglobin, there may not be as much interaction and subsequent injury, Dr. Hill says.
To determine the impact of the genetic mutation on Alzheimer's risk, studies need to be done on more Alzheimer's patients and their families, including taking blood levels of fetal hemoglobin, says Dr. Rodney T. Perry, UAB molecular geneticist and a study corresponding author.
"More studies are needed to confirm the physiologic basis of the interaction," says Dr. Perry who already is working with Dr. Hill to submit a grant to pursue more answers. If they document higher fetal hemoglobin levels in healthy family members with the XmnI polymorphism, the hypothesis that it is providing some sort of protective measure is more likely, says Dr. Perry. Also the amount of disease protection has yet to be determined, he notes. "It may be a small protection."
Either way, the role needs pursuing, Dr. Perry says. "It helps in trying to fill in the pieces of the puzzle of what is going on in the pathogenesis and different etiologies of the disease, how it may come about."
If they are right, the findings could open the doors to treatment approaches that increase fetal hemoglobin levels, Dr. Hill says. One such drug, hydroxyurea, already is used to treat sickle cells patients because fetal hemoglobin will not sickle.
Toni Baker | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy