A new study has identified two proteins that cause patients with Alzheimer's disease to face the double whammy of a lessened blood flow in the brain and reduced rate of brain's ability to remove amyloid beta.
The researchers behind the study have revealed that the two proteins work in tandem in the brain's blood vessels.
The results of the study make the interaction between the two proteins, known for their role in the cardiovascular system, a potential target to tackle both the processes at play in Alzheimer's disease: reduction in blood flow and the build-up of toxic amyloid beta.
"This is quite unexpected. On the other hand, both of these processes are mediated by the smooth muscle cells along blood vessel walls, and we know that those are seriously compromised in patients with Alzheimer's disease, so perhaps we shouldn't be completely surprised," Nature magazine quoted Dr. Berislav Zlokovic, a neuroscientist and a senior author of the study, as saying.
The findings result from a seven-year collaboration between two laboratories- the Center for Neurodegenerative and Vascular Brain Disorders, headed by Zlokovic, which looks at molecular roots of diseases like Alzheimer's and Aab Cardiovascular Research Institute headed by Joseph Miano, Ph.D.
"To some, it might seem odd that a cardiovascular group would intersect with a neuroscience group to study Alzheimer's disease. But there's a great deal of evidence to suggest that Alzheimer's disease is a problem having much to do with the vascular plumbing. And Rochester is the type of institution where partnerships like these are easy to strike up," said Miano.
The current study focuses on two proteins well known to cardiovascular researchers, SRF (serum response factor) and myocardin, which work together within smooth muscle cells that line blood vessels to activate genes that are necessary for smooth muscle to function properly.
SRF binds to certain snippets of DNA called CArG boxes and serves as an anchor, while myocardin piggybacks along and turns on the genes to which SRF sticks. And working together, they act as a master switch that determines whether smooth muscle cells contract, which is one of many ways the body controls how much blood is flowing in the body.
In an earlier study, the researchers has shown that the two proteins are much more active in the blood vessels of brains of people with Alzheimer's disease than in people who do not have the disease. They showed that when they reduced the activity of the proteins, blood flow in the brain increased, and when the genes were more active, blood flow decreased.
In the new study, the researchers went a step further by implicating the molecular duo in the slowed removal of amyloid beta.
They found that when SRF and myocardin work together, they turn on a protein known as SREBP2, which inhibits a molecule known as LRP-1, which helps the body remove amyloid beta. Thus, it means that when SRF and myocardin are active, toxic amyloid beta accumulates.
The findings came primarily from the team's studies of brain cells taken from people who had Alzheimer's disease and comparing them to cells from healthy elderly people.
When compared to the smooth muscle cells from healthy adults, it was found that the cells from patients with Alzheimer's disease had about five times as much myocardin and four times as much SRF, about five times as much SREBP2, and about 60 percent less LRP-1.
This means a reduced ability to remove amyloid beta as cells taken from patients with the disease had only about 30 percent of the ability to remove the substance as cells taken from their healthy counterparts.
By lowering the levels of SRF to the same level that exists in healthy cells, the team found that the cells from Alzheimer's patients improved in their ability to remove amyloid beta, doing it just as well as cells from healthy individuals.
On the other hand, by boosting the levels of SRF and myocardin in the healthy cells, the changes lowered by about 65 percent those cells' ability to remove amyloid beta.
A subsequent literature search turned up findings that the molecules might affect SREBP2, and thus the team could move forward and put the whole picture together.
The new findings appear in an article in the journal Nature Cell Biology.