Potential Alzheimer's Drug Target Identified
Researchers Show How Activated Molecule CD36 Limits Blood Flow to Brain During Alzheimer's Disease, Adding to Dementia
Experiments That Blocked the Receptor Restored Normal Blood Flow, Nourishing Neurons
NEW YORK (April 6, 2011) — As much as they devastate neurons, the pathologic amyloid-beta particles linked to Alzheimer's disease also severely disturb brain blood flow, contributing to dementia, researchers at Weill Cornell Medical College have found.
But there may be some good news, the scientists report in the March 7 early edition of the Proceedings of the National Academy of Sciences (PNAS). They have found a single receptor, CD36, inside affected blood vessels they say is key to the vascular damage, which suggests it could become a beneficial drug target.
The findings have "broad biological and clinical implications," says the study's lead investigator, Dr. Costantino Iadecola, the George C. Cotzias Distinguished Professor of Neurology and Neuroscience at Weill Cornell Medical College and a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
Evidence has been building that Alzheimer's affects brain blood flow, contributing to dementia, and there has been growing interest in trying to understand how this happens and to develop countermeasures, he says.
"Now we know that when amyloid-beta particles — the presumed culprit in Alzheimer's disease — build up in the blood and brain, CD36 sets off a response that than ends up damaging the vessels, which reduces blood flow," Dr. Iadecola says. "This is like what happens in an ischemic stroke in that the brain does not receive sufficient nourishment, except that in Alzheimer's disease brain vessels are not blocked. In Alzheimer's disease there is sufficient blood flow to maintain a low level of brain activity, but not enough to provide the extra energy that brain needs when it becomes more active."
As proof of their discovery, the researchers found that when they disabled CD36 in experimental animals, the brain blood vessels worked just fine, supplying nutrition to neurons affected by Alzheimer's — which helped them function better. "Our study is the first to identify CD36's role in Alzheimer's vascular troubles and to suggest that it could be a target for preventing some of the neuronal dysfunction that is observed in Alzheimer's disease," Dr. Iadecola says.
The CD36 membrane protein is a multipurpose sensor on the surface of some cells, the researchers say. It is used most often by the immune system to detect "invaders," such as bacteria and parasites, and to set off an immediate and complex innate immune response. It is known as a "scavenger" receptor; with several binding sites, it can recognize dozens of different intruders.
But those don't have to be foreign bodies, Dr. Iadecola says. Researchers have recently realized that CD36 can also recognize complex molecules the body makes during the disease process. And the Weill Cornell researchers discovered that these sensors are found in brain endothelial cells that line the inside of brain blood vessels.
While a form of amyloid-beta known as 42 sticks together and builds up into plaques during Alzheimer's disease, a different form, amyloid-beta 40, accumulates in and around brain blood vessels. "Either too much amyloid-beta 40 is being made because of the disease, or it is not being disposed of properly," Dr. Iadecola says.
As the disease progresses, the number of CD36 receptors that line the inside of the brain's blood vessels increases. As part of their inflammatory stress response, the receptors can trigger the release of reactive oxygen species, which are oxygen free radicals that can themselves destroy tissue; this is what happens when increasing levels of CD36 hook on to accumulating amyloid-beta 40 inside and around blood vessels, releasing progressively larger amounts of toxic free radicals, Dr. Iadecola says.
"This is a maladaptive response that causes collateral damage," he says.
Blocking CD36 with antibodies in mice with Alzheimer's restored blood vessel function, he says. Another experiment showed that mice engineered not to express CD36 receptors never developed blood-flow dysfunction.
While blocking CD36 broadly as an Alzheimer's treatment could have unwanted consequences, it might be possible to target "just the binding site on CD36 that amyloid-beta 40 binds to," Dr. Iadecola says.
The work was supported by National Institutes of Health and American Heart Association grants.
The research team included scientists from Weill Cornell Medical College: Laibaik Park, Gang Wang, Ping Zhou, Joan Zhou, Josef Anrather and Sunghee Cho; from McLaughlin Research Institute in Great Falls, Mont.: Rose Pitstick and George Carlson; from Stony Brook University: Mary Previti and William van Nostrand; and from Mayo Clinic, Jacksonville, Fla.: Linda Younkin and Steven Younkin.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals. For more information, visit weill.cornell.edu.