Our roads flood all the time here in Tampa Bay. We’re close to sea level. When it rains, there’s just no place for the water to go, especially at high tide. Storm drains back up, the water level rises, cars stall and traffic stops. The problem isn’t just too much rain, it’s also too little drainage.
Some Alzheimer’s researchers think the same thing may be happening in the brains of people with dementia. According to this theory, the problem isn’t really just too much production of beta amyloid [the sticky protein that forms plaques and is thought to cause Alzheimer’s], it’s also too little “drainage” of that beta amyloid.
Most of the efforts to find a cure for Alzheimer’s have focused on preventing the over-production of beta amyloid. But over the last few years, some scientists have been exploring the idea that in Alzheimer’s brains, the balance between production and elimination of this protein has gone awry.
One of the researchers working to find treatments based on this “drainage” theory is Dr. Malcolm Leissring at The Scripps Research Institute. He is testing various proteases’ [enzymes that break down proteins] ability to destroy beta amyloid and unplug the drain. Much of his research is focused on one specific protease: Insulin-Degrading Enzyme (IDE).
Malcolm Leissring, Ph.D.
Insulin-Degrading Enzyme
“I am interested in all beta amyloid degrading proteases, but IDE is particularly attractive for a lot of reasons,” Dr. Leissring says. “It is one of the few to be linked genetically to Alzheimer’s disease. It appears to be the main protease involved in the degradation of (extracellular) beta amyloid in neurons, because when you delete IDE from cells, you also reduce the amount of beta amyloid degradation by over ninety percent. And there are a lot of tantalizing and unanswered questions about IDE, such as how it gets secreted from cells, which makes it very attractive for research.”
His research fits well with that of other scientists who have found that IDE levels are low in the hippocampus of the brains of people who have been diagnosed with Mild Cognitive Impairment, and even lower in those diagnosed with Alzheimer’s. Low levels of IDE are associated with high levels of beta amyloid.
Progress So Far
Dr. Leissring and his colleagues have shown that mice bred to have increased IDE (or another protease called neprilysin) have reduced levels of beta amyloid in their brains. The increased level of IDE appeared to slow plaque formation in the brains of these mice.
Focusing on the proteases that might increase beta amyloid drainage gives researchers a lot of new possible therapies to prevent dementia. “I don’t think we are anywhere near [human] trials involving IDE,” Dr. Leissring says, “ but there are some exciting results coming out.” One encouraging finding is that increasing the levels of IDE or other proteases (and thereby reducing beta amyloid levels in the brain) might be done via the bloodstream. This could be much safer than attempting to administer a therapy directly to the brain.
Raising levels of IDE will probably not involve adding the enzyme itself to the bloodstream or the brain. According to Dr. Leissring, logistical problems with purifying IDE make it more probable that potential treatments will take a slightly different approach. “All cells make IDE,” he says, “and we can engineer bacteria or other cells to produce it. So it’s easy to produce, but not so easy to purify. I don’t think it will ever be produced on a scale for use in humans. More likely, a drug will be found that affects IDE or influences its expression levels within cells.”
The Insulin Connection
The promise of IDE-related therapies seems to contradict studies that show increasing insulin levels may improve memory for some Alzheimer’s patients. IDE degrades insulin as well as beta amyloid, so increasing IDE levels would be expected to lower insulin levels.
While increasing insulin levels may help some patients in the short term, Dr. Leissring points out that “accumulating evidence suggests that chronically high levels of insulin are not good, neither for diabetes nor for AD. There is a growing body of evidence that suggests that chronically high levels of insulin cause the body to become desensitized to the hormone’s effects---which is exactly what Type 2 diabetes is.”
”Based on our understanding of the causes of Alzheimer’s disease, and the role of IDE in degrading beta amyloid,” he says, “increasing insulin levels would be predicted to increase beta amyloid levels. We actually know that this is true from human studies. But insulin is a potent hormone that has myriad effects on cells, and it just might work for some other reason.”
Some diabetes drugs work to increase insulin sensitivity, rather than raising insulin levels. Researchers at the University of Washington are studying whether these drugs can improve memory in patients diagnosed with Mild Cognitive Impairment.
So, Dr. Leissring thinks simply increasing insulin may not help Alzheimer’s patients. “The approach of using insulin enhancers, on the other hand, seems sound, and there is emerging evidence from animal studies that it might work,” he says.
The Cerebral Amyloid Angiopathy Challenge
Cerebral amyloid angiopathy (CAA) seems to have been the main cause of my father’s dementia and death. In people with CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia and major hemorrhagic strokes like the one Dad had.
Unfortunately, some therapies that decrease the beta amyloid in Alzheimer’s plaques seem to increase the beta amyloid deposits on blood vessels. In theory, Dr. Leissring says, increasing the elimination of beta amyloid would be predicted to prevent both Alzheimer’s and CAA. But in some studies, attempts to dissolve beta amyloid via vaccination have increased CAA and hemorrhages in animals.
A large percentage of Alzheimer’s patients also have CAA. For them, using drugs designed to dissolve amyloid may be risky. “I think we can definitely hope for a preventative treatment for CAA, but the chances of a cure are less certain and will require much more study,” he says.
The Funding Challenge
Dr. Leissring reports that his research is currently funded by “start-up” money from Scripps Florida, funds from the National Institute on Aging (NIA), and a grant from the Ellison Medical Foundation. But even with this funding, he says he’s only been able to start ten percent of his planned projects.
“We are living in an incredible age, where we can do things in a day that would have taken many months just a few short years ago,” he says. “But it really does simply boil down to money (and lab space, ultimately). The more money, the more scientists we can hire and the more experiments can get done.”
Other Alzheimer’s researchers are experiencing the same problems - government and large organization funding seems totally inadequate. It may be that the only way to fill the gap is with private donations. The McNally family, whose father Richard died of Alzheimer’s six weeks after my dad’s death, has started a non-profit fund to support the research of Dr. Leissring and his colleagues. If you’d like to help, please go to The Unforgettable Fund, read the McNally family’s blog, and click on How to Donate.
Mona, with every hard data article you publish, I become more astonished at the amount and quality of research going on, the thoughtfulness of those engaged in the research, the harrowing contradictions involved in this research and, most importantly, THE LACK OF FUNDING AVAILABLE!
What I feel is that the final aspect, the capitalized aspect (pun intended and absolutely appropriate) points to the fact that our economic system is beginning to break down. Bad timing, of course, especially for medical research, but, maybe, just maybe, this formulating crisis will finally gnaw at the asses of our foremost economists and they will begin to understand that continuing to try to fix an economic system based on "enlightened self-interest" isn't the answer: Changing the foundation of the economic system to one of "enlightened community interest" and rethinking what we assume to be our species' primary motivating factors would help.
In the meantime, regarding private funding, has anyone thought to give Bill Gates and Warren Buffet a call???
Posted by: Gail Rae Hudson | October 11, 2006 at 08:17 PM