Active SRF and myocardin turn on SREBP2, slowing the removal of amyloid-beta, says Nature Cell Biology paper.
Researchers say that they have evidence linking two proteins working in the brain’s blood vessels to processes at play in Alzheimer’s disease. The proteins were prevsiouly seen to lessen blood flow in the brain, and the team has now found that they reduce the rate of amyloid beta removal in the brain.
The team found that the proteins, serum response factor (SRF) and myocardin, work together to turn on a molecule known as sterol-responsive element-binding protein 2 (SREBP2). That protein then inhibits low-density lipoprotein-related protein 1 (LRP-1), which helps the body remove amyloid beta under normal conditions. So active SRF and myocardin results in the accumulation of toxic levels of amyloid beta.
Scientists were surprised at the finding, which puts two proteins known for their role in the cardiovascular system front and center in the development of Alzheimer’s disease. “This is quite unexpected,” remarks Berislav Zlokovic, M.D., Ph.D., a neuroscientist and a senior author of the study. “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”
“There’s a great deal of evidence to suggest that Alzheimer’s disease is a problem having much to do with the vascular plumbing,” adds Joseph Miano, Ph.D., senior co-author of the study.
SRF and myocardin work together within smooth muscle cells that line blood vessels to activate genes that are necessary for smooth muscle to function properly. Two years ago, the investigators published a study showing that the two proteins are much more active in the blood vessels of brains of people with Alzheimer’s 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.
This latest report goes further, implicating the protein pair in the slowed removal of amyloid beta. The findings came primarily from the team’s studies of brain cells taken from people who had Alzheimer’s and comparing them to cells from healthy elderly people.
Compared to the smooth muscle cells from healthy adults, the cells from patients with Alzheimer’s disease had about five times as much myocardin, four times as much SRF, about five times as much SREBP2, and about 60 % less LRP-1. That translates into a reduced ability to remove amyloid beta. Cells taken from patients with the disease had only about 30 % of the ability to remove the substance as cells taken from their healthy counterparts.
When the team lowered levels of SRF to the same level that exists in healthy cells, the cells from Alzheimer’s patients improved in their ability to remove amyloid beta, doing it just as well as cells from healthy individuals. Conversely, when the team boosted levels of SRF and myocardin in the healthy cells, the changes lowered by about 65 % those cells’ ability to remove amyloid beta.
In mice, the team found parallel results. When the team boosted SRF or myocardin in healthy mice, those mice had about twice as much SREBP2 in their smooth muscle cells in the brain’s blood vessels. They also had 90% less LRP-1, three times as much amyloid beta in their arteries, and 70% more amyloid beta in their brain tissue.
When the team reduced SRF and myocardin in mice prone to developing Alzheimer’s, those mice had 60% less SREBP2, about four times as much LRP-1, and a 50% reduction in amyloid beta in their blood vessels.
Now the team has turned its attention to studying the role of hypoxia, which seems to play a role in turning on myocardin. They are also searching for molecules that block the joint work of SRF and myocardin.
The research appears in the online December 21 edition of Nature Cell Biology. The findings are the result of a seven-year collaboration between the Center for Neurodegenerative and Vascular Brain Disorders and the Aab Cardiovascular Research Institute.
