For over a century, since the time of the great neuroscientist Alois Alzheimer (1864-1915), medical researchers have been able to identify the devastating effects of Alzheimer's disease by studying the brains of the deceased. A recent innovation, however, allows researchers to study the disease in living brain tissue.
Growing Brain Tissue in a Petri Dish
The fundamental problem in Alzheimer's research has always been that there is no easy way to determine whether a drug has had an effect until after the patient is dead, and by the time a person with Alzheimer's expires, different brain samples tend to look alike. Researchers have been able to test drugs on mice that have a disease similar to Alzheimer's, but results in treating mice do not necessarily translate to results in treating humans.
The breakthrough method of studying Alzheimer's disease arose from a suggestion from Dr. Doo Yeon Kim of the Massachusetts General Hospital's Genetics and Aging Research Unit to his colleague Dr. Rudolph Tanzi that they study brain cells grown in a gel (typically spread over a Petri dish).
Dr. Tanzi took living human brain cells, gave them the genes for Alzheimer's disease, and placed them in a Petri dish. In about a month the cells develop plaque, a substance that looks something like a scrubbing pad. Plaques consist of broken-down and twisted proteins that accumulate between the cells.
In another few weeks, they formed the mass of spaghetti-like neurofibrillary tangles that form the lumps and bumps in the brain that are characteristic of the disease. Tangles appear as nerve cells die. Plaques and tangles interrupt the flow of electrical signals between neurons, and eventually neurons that can no longer communicate with the rest of the brain atrophy and die, leaving behind broken circuits.
Not a Perfect System, But a Major Improvement
A bunch of brain cells growing in a dish in a laboratory, of course, is not functionally equivalent to the human brain. Especially signficant for Alzheimer's research is the fact that cultures of neurons grown in the lab don't include cells from the immune system, which are believed to regulate and accelerate the formation of the tissue-destructive plaques and tangles. However, the ability to observe the formation of plaques and tangles in living brain tissue is of enormous value in testing potential new drugs to treat the disease.
Dr. Tanzi and colleagues' discovery is also important for another reason.
In a few cases, people have died of Alzheimer's and found not to have plaques and tangles when their brains were examined at autopsy. And in a few cases, people have lived free of Alzheimer's but found to have the physical indications of the disease in their brains.
A New Way Of Testing Alzheimer's Drugs
The ability to observe changes in living brain cells has breathed new life into the old theory that the formation of plaques and tangles causes the symptoms of Alzheimer's, and the prevention of plaques and tangles may prevent the symptoms of the disease. In the laboratory, scientists can clearly observe the following sequence of steps:
- The formation of beta-amyloid protein in the fatty layers of individual neurons,
- The accumulation of this "sticky" protein around neurons,
- Blocking of cell-to-cell transmission of electrical impulses by pieces of plaque, and
- The collapse of the tau (rhymes with wow) protein around neurons to form tangles.
Changes to tau protein usually accompany what is believed to the final stage of the destruction of a brain cell.
Strong tau protein is often compared to railroad tracks, speeding the passage of sustenance for the brain. Degraded tau protein looks a little like wrecked railroad tracks, no longer capable of sending substances where they need to go. Brain cells eventually starve, and those that do not starve lose their connections to the rest of the brain.
Five Thousand Possible Cures Now Testable
This new method of observing brain cells does not provide a way to track interaction of brain proteins with the immune system (yet), but it does allow researchers to measure the effects of medications on this part of the pathology of the disease. Even better, it allows researchers to evaluate the potential of new drugs in just a matter of months, compared to a year for each drug tested in mice, and 20 years or more of observing humans diagnosed with the disease.
Dr. Tanzi plans to test 1,200 Alzheimer's disease treatments already on the market, and up to 5,000 more potential treatments over the next few years. Dr. Sam Gandy of the Icahn School of Medicine at Mount Sinai in New York told a New York Times reporter that the new method is “a real game changer” and “a paradigm shifter," and added, “I’m really enthusiastic to take a crack at this in my lab.”
So, Is a Breakthrough Treatment Coming Soon?
Tanzi and other researchers caution that treatments that work in the lab don't necessarily work in people. One medication got good results in treating cultures of brain cells but was found to be too toxic for people.
The new system, however, is not only useful in identifying new drugs that work. It can also be used to study the effects of genetic differences on the course of the disease. Scientists have already started testing brain cells with different APOE genes to see how different genes cause different responses to drugs (and potentially how genetic testing can help doctors prescribe the best drug for their patients). These potential breakthrough drugs probably won't work in absolutely every case of Alzheimer's--some people who have Alzheimer's don't have plaques and tangles--but new drugs that work in many or most cases may be coming in as little as 5 years.