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!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences