The "fifth column" of Alzheimer's: ApoE4
ApoE4 gene and Alzheimer's disease: increased permeability and death of cerebral vessels
LifeSciencesToday based on materials from the University of Rochester: Alzheimer's Gene Causes Brain's Blood Vessels to Leak, DieA well-known genetic risk factor for Alzheimer's disease causes a signaling cascade that ultimately leads to increased permeability of the blood vessels of the brain, which allows toxic substances in large quantities to enter the brain tissue, according to an article in the journal Nature (Apolipoprotein E controls cerebrovascular integrity via cyclophilin A).
Beta-amyloid plaques (green) and brain vessels (red) in Alzheimer's disease (photo: courtesy of Robert Bell).
These results were obtained by a group of scientists from the University of Rochester (University of Rochester), the University of Southern California (University of Southern California) and other scientific centers in the United States, investigating why the ApoE4 gene makes the human body more prone to developing Alzheimer's disease. People with two copies of the ApoE4 gene have about 8-10 times greater risk of developing this neurodegenerative disease.
The researchers found that ApoE4 acts through cyclophilin A, a protein that causes inflammation in atherosclerosis and other cardiovascular diseases. Cyclophilin A opens the door to an attack on the brain observed in Alzheimer's disease.
"We are beginning to understand much more deeply how ApoE4 contributes to the development of Alzheimer's disease," says Robert Bell, PhD, postdoctoral fellow at the University of Rochester, first author of the paper in Nature. "In Alzheimer's disease, in the presence of ApoE4, elevated levels of cyclophilin A cause destruction of the cells lining the blood vessels, just as it occurs in cardiovascular diseases or abdominal aneurysm. This provides a new vascular target for the fight against Alzheimer's disease."
The photo on the left shows destructive proteins (green) lining blood vessels in the living brain tissue of a mouse with the human ApoE4 gene; the introduction of the drug cyclosporin A practically removes dangerous proteins from the brain tissue (right). Photo: University of Rochester Medical Center
The scientists concluded that ApoE4 makes it more likely that large amounts of cyclophilin A accumulate in the cells forming the blood–brain barrier - a network of closely related cells lining the inner surface of the blood vessels of the brain and carefully regulating the output and intake of various substances into the brain.
ApoE4 initiates a cascade of molecular signals that weakens the blood-brain barrier, resulting in increased permeability of blood vessels. This makes it more likely that toxic substances will leak through blood vessels into the brain, damage cells, in particular neurons, and a significant decrease in blood flow due to blocking of blood vessels.
Doctors have long known that changes in the brain in patients with Alzheimer's disease – the death of neurons – begin to develop years and even decades before the onset of symptoms. The events described in Nature correspond to much earlier stages of the development of the disease.
The left photo shows the absence of leakage of a labeled molecule (shown in white), similar in size to many blood proteins, from the blood vessels of a live mouse with the human ApoE3 gene. This process is much more pronounced in mice with the human ApoE4 gene (right). (nature.com)
The idea that vascular problems are at the center of Alzheimer's disease has been championed for more than two decades by the head of the group, neurologist Berislav Zlokovic, MD, PhD, (who previously worked at the University of Rochester Medical Center, and now at the University of South Carolina). For 20 years, Dr. Zlokovich has been investigating how blood flow in the brain of patients with this disease is disrupted and how the blood–brain barrier allows nutrients to enter the brain and toxic substances to leave it.
In Rochester, Zlokovich began a collaboration with cardiologist Bradford Berk, MD, PhD, chief Executive Officer of the University of Rochester Medical Center. Dr. Burke has been studying cyclophilin A for more than two decades. He showed how protein contributes to the destruction of blood vessels and what contribution this destruction makes to the development of cardiovascular diseases - atherosclerosis and heart attack.
"As a cardiologist, I was interested in understanding the role of cyclophilin A in patients suffering from cardiovascular diseases," says Dr. Burke, professor at the Aab Cardiovascular Research Institute. "Now our collaboration in Rochester has led to a discovery that is also important for Alzheimer's disease. The data obtained confirm the basic scientific position – you never know when the knowledge gained in one area will be important in another."
In experiments on mice, scientists found that, compared with the control, animals carrying the ApoE4 gene have five times more cyclophilin A in pericytes – cells that are essential for maintaining the integrity of the blood-brain barrier. Blood vessels in the brain of such mice are destroyed, cerebral blood flow is significantly reduced, and dangerous substances such as thrombin, fibrin and hemosiderin penetrate into the brain tissue.
Blocking the action of cyclophilin A, or knocking out its gene, or the drug cyclosporine A suppressing it reverses pathological changes: blood flow returns to normal, and the pathological penetration of toxic substances from blood vessels into the brain is reduced by 80 percent.
In the scientists' view, the chain of events, briefly, looks like this: in the presence of ApoE4, the amount of cyclophilin A increases; cyclophilin A leads to an increase in the level of one of the molecules associated with inflammation – NF Kappa B; NF Kappa B increases the level of certain types of molecules known as MMP, or matrix metalloproteinases, which are known to, damage blood vessels, reducing blood flow.
In general, this activity leads to a sharp increase in the amount of toxic substances in brain tissues. If this cascade is interrupted at any of several points – by blocking ApoE4, blocking or suppressing cyclophilin A, or inhibiting NF Kappa B or MMP – the blood-brain barrier is restored, blood flow returns to normal, and toxic substances do not enter the brain tissue.
For many years, scientists studying Alzheimer's disease have focused mainly on beta-amyloid, a protein structure that accumulates in the brain of patients. Recent works indicate the importance of other approaches, Dr. Zlokovich believes.
"Our study showed significant damage to neurons as a result of vascular damage that is not associated with beta-amyloid," says Zlokovic. "These injuries are the result of the destruction of the blood-brain barrier and a decrease in blood flow. Beta-amyloid certainly plays an important role in Alzheimer's disease. But it is very important to explore other approaches, perhaps those in which beta-amyloid does not play a central role."
Portal "Eternal youth" http://vechnayamolodost.ru21.05.2012