Better Understanding of Alzheimer’s Cause May Pave Way for New Therapies

New approaches to preventing the formation of the protein that develops into brain plaques, understanding how anti-inflammatory drugs may combat plaque development and how to manipulate a protein important in cell development, represent promising avenues for new therapies for Alzheimer’s patients.

A progressive, degenerative disease of the brain, Alzheimer’s disease affects an estimated four million Americans and is expected to strike 14 million Americans by 2050, according to the Alzheimer’s Association. The new studies were reported today during the 32nd annual meeting of the Society for Neuroscience.

A person may live as long as 20 years after the onset of symptoms and may require care that can exceed $70,000 per year in some areas of the country, notes the Association. In addition, this form of dementia costs American businesses $61 billion annually.

The disease first affects the areas of the brain that control memory and thinking. As it progresses, neurons in other regions of the brain weaken and die. Eventually the person with Alzheimer’s disease will require complete care. If the person has no other serious illness, the loss of brain function itself will cause death.

“It is now widely accepted that the amyloid ß peptide, a naturally occurring protein in the brain, plays a key role in the onset and progression of Alzheimer’s disease,” says Franz Hefti, PhD, of Merck Research Laboratories.

The amyloid hypothesis of Alzheimer’s disease says that higher levels of Aß peptide accumulate in the brains of Alzheimer’s patients through a natural but more rapid process in which the enzymes gamma-secretase and ß-secretase cleave it from the amyloid precursor protein. Fiber-like aggregates of Aß peptide cause neurons to weaken and die.

Thus, it follows from this hypothesis that reducing the concentration of Aß peptide in the brain could slow disease progression, halt it in its tracks or even reverse it, says Hefti.

“Many companies now are engaged in massive efforts to develop agents that would selectively inhibit gamma-secretase and ß-secretase. Several companies have been able to generate drug candidates that are able to reduce Aß levels in animal models of Alzheimer’s disease,” explains Hefti. Many of these are now in large-scale tests for safety, he adds.

“If found safe and effective in clinical trials, new drugs for Alzheimer’s disease may be available in a few years,” he says.

Sometimes, though, scientists find that existing drugs are effective against disease states other than those for which the agents were developed. An example is the sedative thalidomide, which, when taken by pregnant women in the 1960s, resulted in the development of certain birth defects. The drug now has been shown to also work as an anti-cancer agent, helping to deprive tumors of their nourishing blood supply.

In a similar vein, researchers have found that nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen alter production of Aß peptide. “We previously found that NSAIDs do this by reducing production of the longer, 42-amino acid form of Aß,” says Todd Golde, MD, PhD, of the Mayo Clinic Jacksonville. “Although this is a fraction of the Aß peptide that’s normally produced, it’s thought to be more pathogenic than the more abundant 40-amino acid form.”

Golde says he and his colleagues have evaluated NSAIDs approved by the Food and Drug Administration – ibuprofen, sulindac, indomethacin, flurbiprofen, fenoprofen and mecolfenamic acid – for their ability to lower Aß42 in cultured cells and transgenic mouse brains.

“We also have made progress toward identifying the target of these compounds,” Golde says. “It appears that Aß42-lowering agents directly target the gamma-secretase enzyme that carries out the final cleavage of the amyloid ß protein precursor to generate the amyloid ß peptide.”

“We also have identified novel compounds that lower Aß42 more effectively than any of the FDA-approved NSAIDs and act through a non-cyclooxygenase (COX) mediated pathway,” Golde says. “For example, a form of the NSAID flurbiprofen lacks COX activity but was highly effective in reducing Aß42.” A protocol recently has been submitted to the FDA, Golde adds, to evaluate R-flurbiprofen as a treatment for Alzheimer’s disease.

NSAIDs generally act against COX 1 and COX 2 enzymes to reduce inflammation and associated pain. Inhibiting production of COX 2 is preferable, because COX 1 helps maintain the stomach lining (most traditional NSAIDs inhibit production of both enzymes, although COX 2 is the majority of the enzyme at the site of inflammation). Extended use of traditional NSAIDs is associated with potentially severe gastrointestinal side effects, such as gastric ulcers and bleeding. Drugs that are selective COX 2 inhibitors tend to cause fewer gastrointestinal complaints.

“At the present time, however, it’s unknown as to whether the effect of NSAIDs in Alzheimer’s disease is due solely to the Aß42-lowering effect, their anti-inflammatory properties, some unknown mechanism or a combination of factors,” Golde explains.

Scientists also have discovered that totally inhibiting the production of gamma-secretase could have significant side effects, such as faulty processing (breakdown) of the Notch receptor protein. “Notch breakdown is needed for the production of many cell types,” says Raphael Kopan, PhD, of Washington University School of Medicine in St. Louis.

In 1998, Kopan and his colleagues determined how the Notch1 protein, which resides on cell surfaces, influences gene activity to drive developmental decisions. “If a drug prevents Notch from working, it will adversely affect stem cells that regenerate the blood system, which will have a faster, more devastating impact on someone’s health than a slowly progressing disease like Alzheimer’s,” says Kopan.

In previously published research, Kopan and his colleagues showed that exposing cultured mouse organs to continual drug therapy with gamma-secretase inhibitors prevented T cells, important immune system components, from developing properly. Notch1 also is crucial in the early development of neurons, he says.

The ability to test potential new therapies for such effects would be useful, says Kopan. “This is a way to evaluate drugs for toxicity before human testing. Doses that reduce activity of this enzyme without eliminating it might be safest.”

Kopan also has shown that a part of the Notch receptor hangs inside the cell so when it’s clipped off it finds its way to the nucleus, where it physically associates with the transcription machinery.

He and his colleagues also have determined that Notch and presenilin-1 physically interact and that presenilin-1 may play a role in Notch processing. Presenilin-1 is a protein also found to have an association with Alzheimer’s disease, particularly its early-onset familial form.

Kopan’s current research activities involve learning how presenilin/ gamma-secretase functions and if Notch can act independently of y-secretase. He hopes to uncover new ways of treating Alzheimer’s and other diseases that may be related to presenilin activity.

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