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Attacking Alzheimer's

By Sean Henahan, Access Excellence

New York , NY (8/03/01)- Decades of painstaking basic research in the laboratory into the pathogenesis of Alzheimer's disease may soon pay off in the form of new screening methods and treatments for the devastating neurological disorder. Recent advances include new vaccine and drug candidates, as well as surgically based gene therapy.

One in 10 persons over 65 and nearly half of those over 85 have Alzheimer's disease. Today, four million Americans have Alzheimer's disease. Unless a cure or prevention is found, that number will jump to 14 million by the year 2050. Worldwide, it is estimated that 22 million individuals will develop Alzheimer's disease by the year 2025 Source: Alzheimer's Association

Alois Alzheimer, the German neurologist for whom the illness is named, first noticed the presence of tangled plaques of tissue in autopsy specimens of Alzheimer's patients 1906. Nearly 100 years later, researchers are convinced that these plaques do indeed lead to the development of damaged brain tissue, producing the characteristic dementia of the disease. Many labs are investigating the nature of this amyloid plaque and potential methods for blocking its formation.

When research revealed that mutations in amyloid precursor protein (APP) resulted in increased production of beta-amyloid peptide (A-beta-42) found in virtually all amyloid plaque of Alzheimer's patients, investigators decided to make a vaccine with a synthetic form of AB42 to see if it might confer protection against the disease. Early animal studies suggested that the vaccine did indeed appear to protect transgenic "Alzheimer" mice. This led the vaccine developer, Elan Pharmaceuticals, to test the safety of the vaccine in a small, Phase I human clinical trial. In July ('01), the company announced that the vaccine appeared to be safe and well tolerated in humans. A phase II study is now being prepared that will begin to determine whether the vaccine provides any therapeutic or prophylactic effects.

Meanwhile, researchers at the NYU School of Medicine have developed a different vaccine candidate that they believe may be even better, at least from a safety standpoint. Reporting in the current issue of the American Journal of Pathology, the NYU team says they have successfully immunized mice against Alzheimer's. The NYU vaccine, based on a fragment of amyloid protein, reduced the amount of amyloid plaque in the brains of mice by 89 percent. It also reduced the amount of soluble amyloid beta in the brain by 57 percent.

"Our study clearly shows that the vaccination approach is a powerful one that shows great promise for Alzheimer's disease. And significantly, our approach appears to be nontoxic," says. Thomas Wisniewski, M.D., Associate Professor of Neurology, Pathology, and Psychiatry at NYU School of Medicine.

The NYU researchers believe that the Elan vaccine now in human trials could be toxic to nerve cells in the brain. They believe it might trigger the formation of fibrils of plaque-forming amyloid. And they believe their vaccine candidate may be safer:

"We believe that our peptide vaccine isn't toxic to nerve cells because it doesn't aggregate into clumps; it remains in solution," said Blas Frangione, M.D., Ph.D., Professor of Pathology at NYU School of Medicine.

Human clinical trials with the NYU vaccine could begin within one year.

DESIGNER PLAQUE BUSTER

Researchers at the University of Illinois at Chicago are working on a different approach. They have designed and synthesized a potent compound that
blocks the action of one of two proteases that play a critical role in plaque creation. This enzyme, memapsin 2, severs a longer protein in the brain called amyloid precursor protein, or APP, to produce beta-amyloid, the major component of the plaques that lead to the development of Alzheimer's disease. The new inhibitor compound attracts memapsin 2 and keeps it from cutting APP, potentially a useful way to halt accumulation of beta-amyloid in the brain.

Left: Amyloid Plaque in Brain of Alzheimer's Patient

"This enzyme is probably the most exciting target for an Alzheimer's drug," said Arun Ghosh, professor of chemistry. Ghosh led the Chicago research team in collaboration with Jordan Tang, head of the Protein Studies department at the Oklahoma Medical Research Foundation in Oklahoma City.

While the finding is promising, it is only a first step towards developing a therapeutic agent, Ghosh cautioned:

"That was a preliminary inhibitor. It's a big one, containing eight peptides - a size that is inconceivable to be a drug candidate. Peptide-like compounds never make useful drugs because they're metabolically unstable, they're insoluble and, perhaps the biggest problem in Alzheimer's patients, they're hard to deliver in the human brain."

Nonetheless, the new finding will guide researchers in their search for smaller, more potent inhibitors based on the same princple.That in turn could lead to effective treatments for Alzheimer's disease.

GENE SCREEN

In recent years genetic researchers looking for a way to identify those at risk for Alzheimer's disease have zeroed in on a gene called APOE4.People with this gene are believed to be at increased risk for developing the disease. Those with multiple copies of the gene appear to be at even greater risk. Researchers from the University of Pittsburgh reported recently the identification of yet another genetic risk factor for susceptibility to Alzheimer's disease.

After following 300 first-degree relatives of 189 Alzheimer's patients for ten years, the researchers identified a small area of chromosome 10 that, when combined with the previously identified APOE E4 gene, appears to significantly increase a person's risk of developing the disease. The combination of the genes is associated with a 16-fold increase in the risk of AD among first-degree relatives. These findings may also provide new molecular targets for therapeutic drug development . They could also help researchers to determine which patients might benefit the most from new treatments for the disease.

HUMAN BRAIN TRANSPLANTS

No investigators are farther out on the frontier of Alzheimer's research than those at UC San Diego. In April of this year, a team of physicians surgically implanted genetically modified tissue into the brain of an Alzheimer's patient. The surgery was the beginning of an experimental gene therapy protocol.It was the first attempt to use human gene therapy to treat a disease of the nervous system. The gene therapy was designed to deliver nerve growth factor (NGF) a naturally occurring protein, directly to the part of the brain affected by the disease.

Months before the surgery, the researchers inserted NGF genes into tissue samples obtained from the patient. These genetically engineered cells were then cultured. Over time, the modified cells began producing large quantities of NGF.

In earlier animal studies, this approach produced improvements in cholinergic function. It will be some time before the researchers know if the procedure is beneficial in humans. The UCSD team will continue to test the procedure in selected patients.

"NGF gene therapy is not expected to cure Alzheimer's disease, but we hope that it might protect and even restore certain brain cells and alleviate some symptoms, such as short-term memory loss, for a period that could last a few years," noted UCSD neurologist Mark H. Tuszynski, MD, Ph.D.

References

The NYU research appeared in the August 2, 2001 issue of the American Journal of Pathology. The Chicago research was reported in the American Chemical Society's Journal of Medicinal Chemistry. The Pittsburgh research was published in Molecular Psychiatry 2001 Volume 6, number 4, pages 413-419. The UCSD team published animal data in the Sept. 14, 1999 and February 2000 issues of the Proceedings of the National Academy of Sciences.

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