Researchers at the University of Pennsylvania School of Medicine have shown that impaired function and loss of synapses in the hippocampus of a mouse form of Alzheimer’s disease (AD) is related to the activation of immune cells called microglia, which cause inflammation. These events precede the formation of tangles – twisted fibers of tau protein that build up inside nerve cells – a hallmark of advanced AD. The researchers report their findings in the February 1 issue of Neuron.
The microglia might cause the tau protein to get all bent out of shape. Then the tau proteins can't get transported to stabilize microtubules. That causes the loss of the transport mechanism and the nerves collapse since needed stuff isn't getting delivered.
So why do the microglia get activated in the first place? Even before the tau protein gets bent out of shape it accumulates. But why does the tau protein accumulate? This report does not answer that question but one potential answer is that aged nerve cells cease to make enough energy to run their internal transport and internal trash destruction mechanisms.
“Abolishing the inflammation caused by the accumulation of the tau protein might be a new therapy for treating neurodegenerative disorders,” says senior author Virginia Lee, PhD, Director of the Center for Neurodegenerative Disease Research. “This work points the way to a new class of drugs for these diseases.”
In addition, the immunosuppressant FK506 diminishes neuron loss and extends the life span of the transgenic Alzheimer’s mice. Normally only 20 percent of these mice survive by one year. With FK506, 60 percent of the mice were alive by one year.
But methods to suppress the immune response, while potentially useful for therapeutic purposes, probably won't get at the original cause of Alzheimers. Decreased blood flow might be the real cause of Alzheimer's Disease.
The latest findings from the University of Rochester Medical Center mesh not only with Dr. Azheimer's initial observations but also with new findings from today's best imaging technologies. While the first visible symptom of Alzheimer's may be a person forgetting names or faces, the very first physical change is actually a decline in the amount of blood that flows in the brain. Doctors have found that not only is blood flow within the brain reduced, but that the body's capacity to allocate blood to different areas of the brain on demand is blunted in people with the disease.
"A reduction in blood flow precedes the decline in cognitive function in Alzheimer's patients," said Berislav Zlokovic, M.D., Ph.D., professor in the Department of Neurological Surgery and a neurovascular expert whose research is causing scientists to consider the role of reduced blood flow in Alzheimer's disease.
"People used to say, well, the brain is atrophying because of the disease, so not as much blood as usual is needed. But perhaps it's the opposite, that the brain is dying because of the reduced blood flow," he added.
Perhaps this phenomenon is at work on a lesser scale with many people whose minds decay to a lesser extreme without getting diagnosed with Alzheimer's. If so then a treatment to prevent this would likely reduce the rate of cognitive decline even in people who never are going to get Alzheimer's.
Look at how they were able to make this discovery. It is only because gene array chips allow the measurement of the activity of thousands of genes that these scientists were able to get clues that the problem was in the vascular system.
The first step in the study came when Zlokovic's team compared the activity of genes in the brain from several people with Alzheimer's who had died, to that of several people without the disease who had died. It's a type of study widely done now by scientists looking at a host of diseases, using vast gene arrays that can tell how active thousands of genes are in a part of the body.
Scientists have been chasing after the cause of Alzheimer's Disease for decades. But now they have the technological tools to figure out the puzzle and they are coming up with answers that eluded them until now. Think about what that portends for the future of biomedical research into the causes of diseases. The gene chips, microfluidic chips (think "lab on a chip"), and other tools are going to keep getting better at a rapid rate.
The scientists were able to narrow their search down to two key genes that regulate contraction of muscle cells found in arteries.
As Zlokovic perused the list of genes whose activity differed depending on whether the person had Alzheimer's or not, he recognized that several play a role in constricting the arteries. He asked colleague Joseph Miano, Ph.D., a cardiovascular researcher and expert on the smooth muscle that makes up part of the arteries, to take a look.
Miano recognized the group as genes that are all controlled by one of two master regulators of gene activity in smooth muscle cells. Those proteins, myocardin and SRF (serum response factor), are well known for the control they exert on blood vessel walls. Working together, the two are the chief players that regulate how much the smooth muscle cells inside the arteries contract. The more the cells contract, the narrower the artery becomes, and the less blood that flows.
They discovered that SRF and myocardin are more active in Alzheimer's brains, that greater activity of SRF and myocardin causes blood vessels to contract, and that silencing SRF allowed blood to flow more freely. So we might be able to prevent Alzheimer's with a drug that turns down SRF or myocardin.
Now we need a way to detect at an early stage that SRF and myocardin are overactive. You do not want to lose a big chunk of your brain before getting diagnosed with Alzheimer's. We also need to know why these genes become overactive in the brains of some old people. With that knowledge scientists could develop ways to prevent the whole chain of events from ever getting started.
Thanks to Lou Pagnucco for the tip on the second article.
|Share |||Randall Parker, 2007 February 04 07:06 PM Brain Alzheimers Disease|