An antioxidant found in the popular drink prevented Alzheimer’s-like damage in the brains of mice that had been genetically programmed to develop the disease process, researchers at the University of South Florida report.

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly in the United States, affecting 4.5-5 million adults -- 10 times more than those affected by Parkinson's disease. Starting with mild memory problems and ending with severe brain damage, Alzheimer's usually begins after the age of 60, the risk increasing with age.

Dramatic Decrease in Plaques

The green tea antioxidant, called epigallocatechin-3-gallate (EGCG), appears to block the initial process by which the Alzheimer’s-related protein beta-amyloid is formed in brain cells. An abnormal accumulation of beta-amyloid can lead to nerve damage and memory loss.

The USF researchers found that EGCG decreased production of the protein both in cell cultures and in a mouse model for Alzheimer’s disease.

After treating Alzheimer’s mice for several months with daily injections of pure EGCG, the researchers observed a dramatic decrease -- as much as 54 percent -- of brain-clogging Alzheimer’s plaques.

"The findings suggest that a concentrated component of green tea can decrease brain beta-amyloid plaque formation," says senior study author Jun Tan, PhD, MD, director of the Neuroimmunology Laboratory at the Silver Child Development Center, USF Department of Psychiatry.

"If beta-amyloid pathology in this Alzheimer’s mouse model is representative of Alzheimer’s disease pathology in humans, EGCG dietary supplementation may be effective in preventing and treating the disease," he adds.

New Generation of Dietary Supplements

Green tea contains many antioxidants, including flavonoids that can protect against free radical damage to the brain. But there are other flavonoids in green tea that actually counter the ability of naturally occurring EGCG to prevent the harmful build-up of beta-amyloid. Thus, drinking green tea likely would not have a beneficial effect through the same mechanism that EGCG works, Dr. Tan explains.

"This finding suggests that green tea extracts selectively concentrating EGCG would be needed to override the counteractive effect of other flavonoids found in green tea," notes study co-author Doug Shytle, PhD. "A new generation of dietary supplements containing pure EGCG may lead to the greatest benefit for treating Alzheimer’s disease."

Humans probably would need 1500 to 1600 mg of EGCG daily to approximate the injection dosage that benefited the Alzheimer's mice, according to Dr. Tan.

The USF researchers plan to study whether multiple oral doses of EGCG can improve memory loss in Alzheimer's mice along with reducing their Alzheimer's plaque burden. "If those studies show clear cognitive benefits," says Dr. Tan, "we believe clinical trials of EGCG to treat Alzheimer's disease would be warranted."

Cognitive Comeback

In a separate study published in Nature Neuroscience, researchers were able to reverse memory loss in mice that had been genetically engineered to develop Alzheimer's disease by reducing the amount of an enzyme crucial to its development.

"What we are showing is a proof of principle that stopping the synthesis of a protein that is necessary for the formation of the telltale plaques reverses the progression of the disease," says Inder Verma, professor in the Laboratory for Genetics at the Salk Institute for Biological Studies.

"And, more importantly, the cognitive function of these mice -- which had already been impaired -- has now recovered," Verma notes.

In the past, gene therapy has been used mainly to deliver normal genes into cells to compensate for defective versions of the gene causing disease.

In this study, which was a close collaboration between researchers at the Salk Institute and scientists at the University of California in San Diego, gene therapy was used to silence a normally functioning gene.

By exploiting a mechanism called RNA interference, researchers were able to turn down the gene that helps produce the characteristic amyloid plaques that are one of the hallmarks of Alzheimer's disease.

"Within a month of treatment, mice that had already suffered memory deficits could learn and remember how to find their way through a water maze," says co-author Robert Marr, a post-doctoral researcher in Verma's lab.

"It appears that these mice can come back from a very severe level of disease progression," adds first author Oded Singer, also at the Salk. "This is a very important finding, because humans are usually diagnosed when the disease has already progressed relatively far."

But it is too early to make direct comparisons with the human disease, he says, since mice ordinarily don't develop its symptoms unless they are genetically engineered to do so.

Dimmer Switch

Amyloid plaques, which are insoluble protein clumps in the brain, can precede the onset of dementia by many years. These plaques are formed when enzymes cleave the amyloid precursor protein (APP), releasing the toxic beta amyloid fragments that clump together to form the sticky plaques. One of the enzymes doing the cleaving is called beta secretase or BACE1.

Although the production of beta amyloid occurs in all brains, healthy brains are able to clear away excess amounts. Brains of people with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation.

For several years now, drug companies have been trying to find a drug that inhibits BACE1 and thus prevent beta amyloid from building up in brains of people with Alzheimer's disease. So far, the goal has remained elusive.

Instead of looking for chemical compounds to inhibit BACE1, Oded Singer, collaborating with the laboratories of Fred H. Gage at the Salk Institute and lead author Eliezer Masliah at UCSD, resorted to small biological molecules, called short interfering RNA, or siRNA, which derail the process of translating genes into proteins. They work like a dimmer switch, reducing the amount of available gene product -- in this case the enzyme BACE1.

A modified lentivirus, which has been developed in Verma's lab, delivered the siRNAs into the brain cells of the transgenic mice that were producing vast amounts of human beta-amyloid and whose brains where littered with plaques.

"When you compare the brains of treated and untreated mice, the difference is striking," says Singer. "Silencing BACE1 reduced the number and size of plaques by two thirds within a month, which is incredibly fast."