ARTICLE IN BRIEF
Investigators identified an innate immunity receptor, CD36, as a major player in allowing amyloid to take up residence in the blood vessels of the brain.
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A team of scientists from Weill Cornell Medical College, Rockefeller University, the Mayo Clinic in Florida, and the McLaughlin Research Institute in Montana, have discovered that an innate immunity receptor, CD36, has a role in trafficking amyloid-beta in the blood vessel and has a direct role in the vascular accumulation of the toxic peptide contributing to the brain cell damage that leads to cognitive decline.
Costantino Iadecola, MD, director of the Brain and Mind Research Institute at Weill Cornell, and his colleagues were interested in how damaged blood vessels loaded with the sticky amyloid peptide contribute to the pathology of Alzheimer's disease (AD), and worsen cognitive decline. There has been growing evidence that vascular damage has a role in AD. It has also been known that amyloid accumulates in the blood vessels, restricting the flow of oxygen to the brain. This results in cerebral amyloid angiopathy (CAA), a condition that also leads to dementia independently of AD. But just how this process works has been a mystery — until now.
In a study that first appeared online Feb. 4 before the print edition of the Proceedings of the National Academy of Sciences, the investigators identify CD36 as a major player in allowing amyloid to take up residence in the blood vessels of the brain. They created an animal model in which CD36 was eliminated in mice overexpressing a mutated form of the amyloid precursor protein (APP) and found that it dampened the accumulation of amyloid in the blood vessels, and slowed or reversed some of the cognitive deficits in these animals.
CD36 sits on the surface of immune cells and endothelial cells in blood vessels. It functions normally to detect molecules that are a threat to the body. Some of these molecules are from infectious organisms but some proteins that are abnormally produced by the body can trigger an immune response against self. These molecules are called Danger Associated Molecular Patterns, or DAMPS, and include amyloid-beta peptide. Under such circumstances, the immune system sends out messages that lead to an increase in inflammatory molecules and oxygen free radicals. This attack against self results in damage to blood vessels in the brain, which, as suggested by the present study, impedes the normal clearance of amyloid. This process leads to accumulation of the amyloid-beta peptide in the blood vessels.
The scientists believe that targeting CD36 may be a novel approach to treating AD. Such an approach could also be used to boost the effectiveness of the amyloid immunotherapies that are now in various stages of testing. Some of the side effects that have led to problems in the clinical trials are due to amyloid accumulating in blood vessels, said Dr. Iadecola.
STUDY METHODOLOGY, RESULTS
Once they identified the immune receptor's involvement in the effects of amyloid-beta on the function of cerebral blood vessels, the researchers designed a study to eliminate the receptor in mice with APP overexpression. They followed the animals over time and conducted various tests to measure cognitive decline. They also looked at the AD pathology.
What they found was surprising, said Dr. Iadecola. As suspected, the mice did have less amyloid build-up in their blood vessels. But the AD pathology in the brain parenchyma was still progressing with massive amyloid-filled plaques. Moreover, behavioral tests showed that the animals were cognitively on par with animals in much earlier stages of disease. The animals were tested over a two-year period.
In addition to behavioral tests — a maze that allowed them to study an animal's interest in exploring — the researcher conducted vascular reactivity studies to show that the blood vessels were healthier in APP mice lacking CD36. In normal APP mice, pericytes in the blood vessel wall are swollen and abnormal, but this phenotype is rescued by CD36 deletion. Lipoprotein receptor 1 (LRP-1) that normally helps clear amyloid-beta from the blood vessels was reduced in the APP mice, an effect that was prevented by lack of CD36.
“The blood vessels of APP mice lacking CD36 looked and functioned more like those of normal mice,” said Dr. Iadecola. “Although the brain parenchyma was heavily loaded with plaques, the amyloid was not able to induce vascular damage and cognitive impairment.”
“This tells us a lot about Alzheimer's,” said Dr. Iadecola. “If reducing amyloid burden in the cerebral blood vessels was able to preserve cognitive function in animals, perhaps this could be a potential way of preventing cognitive decline in patients.”
Normally, the amyloid-beta peptide is cleared from the brain, in large part through blood vessels. Many AD patients also have CAA but it is not yet clear how common CAA is in the general population of elderly patients without AD, although new imaging approaches have now revealed that CAA is more common then previously believed.
Designing drugs that block CD36's effects on amyloid-beta will not be easy. CD36 has so many roles in the body that it could be dangerous to block the scavenger protein from doing other jobs in the body. Dr. Iadecola and his colleagues are searching for such selective compounds now.
IRONIES AND OPPORTUNITIES
“There are a lot of ironies here,” said Steven M. Greenberg, MD, PhD, professor of neurology at Harvard Medical School and the John J. Conway endowed chair in neurology, and director of hemorrhagic stroke research at the Massachusetts General Hospital. “In our great-grandparents' generation, it was thought that dementia was caused by hardening of the arteries and in our grandparents' generation, Alzheimer's was thought to be responsible for most dementia. Now, we are beginning to understand the vascular contribution to Alzheimer's. Dementia from a single cause is rare.”
Dr. Greenberg and his colleagues study cerebral amyloid angiopathy burden in people with and without dementia. They are using Pittsburgh Compound B (PiB) to look at vascular amyloid and have found PiB straining and sites of bleeding and links between PiB binding and white matter hypertensities. “There is a lot of interplay between vascular and amyloid pathology,” said Dr. Greenberg.
David J. Werring, MD, a leader in clinical neurology and honorary consultant neurologist at UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square in London, is also an expert on CAA and small vessel diseases. “This idea that vascular problems increase the risk for AD has been growing in acceptance. We have known for a long time that vascular amyloid-beta and brain plaque amyloid-beta are often associated, but the vascular amyloid-beta has not featured in diagnostic criteria for AD, and the functional significance has not received as much attention as the amyloid-beta within the brain, in plaques.
“It has been difficult to tease out separate mechanisms specifically influencing the vascular amyloid-beta component in AD,” said Dr. Werring. “This study is really exciting as it shows a specific reduction in vascular amyloid-beta deposition (but, importantly, not brain plaque amyloid-beta) in response to manipulating an immune receptor (CD36) known to be important in amyloid-beta trafficking.
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“Transgenic mice programmed to overexpress amyloid-beta had less severe vascular amyloid if they lacked the CD36 receptor, with preservation of an important amyloid-beta clearing mechanism involving another receptor, LRP-1. Crucially, the study takes this observation further by showing that selective reduction of the severity of vascular amyloid-beta alone leads to improved neurovascular regulation and cognitive function.”
The key implication, Dr. Werring added, “is that vascular amyloid-beta deposition is functionally important (independent of plaque amyloid-beta), and could be selectively targeted for treatment in AD. The study also suggests a new disease mechanism in CAA occurring outside the setting of AD.”
The cause of sporadic CAA is unknown, yet it is an important cause of cerebral hemorrhage (the most deadly stroke type) and cognitive impairment in its own right, Dr. Werring said. “This work opens the door for new therapeutic targets in CAA, a disease currently with no effective treatment.”
If CD36-receptor signaling could be down-regulated — for example, by antibodies blocking the site where amyloid beta binds to it — this may reduce vascular amyloid deposition and improve the function of the small vessels affected by CAA, Dr. Werring said.
There have been trials of immunotherapy involving both active and passive immunization with antibodies targeting amyloid beta in AD, and the hope is that if these agents can safely clear amyloid (including vascular amyloid) from the brain, they may also be helpful in clearing amyloid in CAA, he added.
“Although experimental data have been promising, a major concern is that because CAA (with or without co-existing AD) makes blood vessels fragile and leaky, rapid clearance of amyloid might actually worsen inflammation and bleeding from CAA-laden vessels,” Dr. Werring said. “There is some evidence from brain imaging suggesting this, but exactly how much of a problem this could be is not yet known and requires further study.” Therefore, protection of the blood vessels by targeting CD36 may be a valuable strategy to counteract the deleterious vascular effects of CAA.
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