New Target for Alzheimer’s

By ASTARA MARCH

New insight into a misfolded protein and an anti-inflammatory drug used in transplant procedures may make major contributions to the treatment of Alzheimer’s disease, according to researchers at the University of Pennsylvania School of Medicine in Philadelphia.

Virginia Lee and John Trojanowski, the study’s lead authors, explained that Alzheimer’s disease is the most common form of dementia, a group of conditions that all gradually destroy brain cells and lead to the progressive decline of mental functioning.

They said that two events must occur for Alzheimer’s to develop. First, amyloid proteins, which are normally found in the body, start dividing improperly and produce beta amyloid, a neurotoxic substance that builds up on the outside of nerve cells in the brain and causes inflammation that destroys them.

Second, neurofibrillary tangles occur inside the brain’s nerve cells, also causing inflammation and disrupting the pathway that brings nourishment to the synapses. Synapses are the charged spaces between nerve cells that allow them to communicate by sending chemical messages to each other. When the synapses can’t function, the messages don’t get through, and mental functioning deteriorates rapidly, accompanied by changes in personality, anxiety, delusions and hallucinations.

John Breitner, an Alzheimer’s researcher at the University of Washington in Seattle, thought the new work held significant promise for the future.

Anything that prevents the formation of tangles is extremely important, Breitner told United Press International. This work brings together two very interesting and important lines of thought about what causes AD — the tau story and the inflammation story — and suggests a new way in which inflammatory mechanisms may be involved. It definitely has potential for treatment.

While a great deal of research has focused on ways to clear beta amyloid from the system, Lee and Trojanowski decided to explore what was happening inside the cells to cause the neurofibrillary tangles.

Using specially bred mice, they discovered that a protein called tau plays a major role in this process. The tau protein braces the microtubules that bring important nutrients to the synapses, much as cross-ties stabilize train tracks.

In Alzheimer’s, tau starts being produced in bizarre forms that can’t perform the protein’s structural functions and the microtubules collapse, depriving the synapses of nourishment and short-circuiting thought.

As more and more misfolded, non-functioning tau protein is produced, it builds up inside the neurons and forms fibers that tangle and block the microtubules completely as well as causing inflammation that leads to cell death.

In the second part of their work they tried to stop this inflammation using a powerful drug called FK506, an immunosuppressant given to transplant patients to combat organ rejection.

The mice they had developed to mimic the symptoms of Alzheimer’s usually showed changes in mental status by six months, produced neurofibrillary tangles by nine months, and only 20 percent were still alive at one year. When they were given FK506, fewer of their brain cells died, and 60 percent survived to age 1.

It’s early days yet, Lee told UPI, but we are very encouraged by what we’ve found. Identifying the tau protein as the culprit in synapse loss gives us a new target for therapy, and FK506 is an interesting lead compound in our search for good Alzheimer’s therapies.

Lee explained that FK506′s established safety record in human beings will make further testing go more quickly. Although the drug can produce neurological symptoms at high doses, these symptoms disappear when the drug is discontinued, which leads Lee and her colleagues to think that other compounds in its class may provide the drug’s benefits without its side effects.

Both Lee and Breitner said an important focus of their work was finding a way to diagnose Alzheimer’s before symptoms developed so mental deficits could be prevented altogether, and Breitner revealed that there was actually a real possibility such a tactic would be successful.

There is considerable evidence that the causal mechanisms in AD are silently operative for at least 20 years before dementia symptoms appear, Breitner explained. This creates an enormous opportunity for prevention. Anti-inflammatory agents, such as FK506, are one of several classes of drugs under active investigation for such an intervention.

Lee said the growing number of Alzheimer’s researchers around the world was also spurring progress in the field very rapidly.

On the hundredth anniversary of Alois Alzheimer’s first case presentation (Nov. 5, 2006), we held a meeting in Tubingen, Germany, in the same room in which he made his announcement, Lee told UPI. Between 60 and 70 researchers reported on all the work being done in the field at the current time and we were all very encouraged. It was a wonderful celebration!

Lee and Trojanowski collaborated with researchers in Japan and China on their study, which can be found in the Feb. 1 issue of the journal Neuron.