New Findings About Brain Proteins Suggest Possible Way To Fight Alzheimer's

The action of a small protein that is a major villain in Alzheimer's disease can be counterbalanced with another brain protein, researchers at UT Southwestern Medical Center have found in an animal study.The findings, available online in the journal Proceedings of the National Academy of Sciences, suggest a promising new tactic against the devastating illness, the researchers said.

The harmful protein, called beta-amyloid, is found in the brain and, when functioning properly, suppresses nerve activity involved with memory and learning. Its normal function can be likened to a red traffic light, restraining nerve cells from getting overexcited when they receive stimulating signals from neighboring cells. People with Alzheimer's disease, however, accumulate too much beta-amyloid – the traffic light gets stuck on "red" and nerve cells become less responsive.

Another brain protein, called Reelin, acts as a "green light," stimulating nerve cells to respond more strongly to their neighbors' signals.

The new study shows that applying Reelin directly to brain slices from mice prevents excess beta-amyloid from completely silencing nerves.

"If we can identify a mechanism to keep the nerve cells functioning strongly, that might provide a way to fight Alzheimer's disease," said Dr. Joachim Herz, professor of molecular genetics and neuroscience at UT Southwestern and the study's senior author.

In the study, the researchers recorded electrical currents in the mouse hippocampus, an area of the brain associated with learning and memory. From their experiments they determined that Reelin and beta-amyloid interact with the same protein complex, called an NMDA receptor, which plays an important role in coordinating chemical signals between adjacent nerve cells.

They found that Reelin activates and strengthens the response of the NMDA receptor. In the presence of too much beta-amyloid, the receptor migrates into the cell, reducing the cell's sensitivity to incoming signals. By contrast, in strong concentrations of Reelin, the receptor remains active and the cell has the green light to continue receiving normally.

Dr. Herz said the study is especially important because this mechanism involves another protein involved in Alzheimer's called ApoE4, which is the primary risk factor for the most frequent late-onset form of the disease. The receptor that binds to ApeE molecules also binds to Reelin, and is part of the red-light/green-light complex that controls the sensitivity of the NMDA receptors.

"These results imply that Reelin, ApoE and beta-amyloid converge on the same molecular mechanism, which is critical in the Alzheimer's disease process, and Reelin may be a common factor to fight both beta-amyloid and mutated ApoE," Dr. Herz said. "This study establishes a rationale that ApoE receptors have an action that can keep the Alzheimer's disease process at bay by preventing damage in the first place."

The researchers are currently studying the role of ApoE4 in this mechanism. Mimicking or preserving normal Reelin function to stimulate the ApoE receptors might provide a path to stave off the disease, Dr. Herz said.

Other UT Southwestern authors included lead author Dr. Murat Durakoglugil, assistant instructor of molecular genetics; graduate student Ying Chen; Dr. Charles White, professor of pathology; and Dr. Ege Kavalali, associate professor of neuroscience.

The study was funded by the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation and the Humboldt Foundation.

Physicians Bust Myths About Insulin

People diagnosed with type 2 diabetes often resist taking insulin because they fear gaining weight, developing low blood sugar and seeing their quality of life decline.A study recently completed at UT Southwestern Medical Center suggests that those fears are largely unfounded and that patients and physicians should consider insulin as a front-line defense, as opposed to a treatment of last resort for non-insulin-dependent diabetes.

"We found that those patients who received insulin initially did just as well, if not better, than those who didn't receive insulin," said Dr. Ildiko Lingvay, assistant professor of internal medicine at UT Southwestern and lead author of the study appearing online and in a future issue of Diabetes Care. "This reinforces the idea that insulin treatment is a viable and safe option for patients, even in the very initial stages of their diagnoses.

"There is a myth out in the community, especially among certain ethnicities, that insulin is the last resort, and that somebody started on insulin is going to die," Dr. Lingvay added. "We as physicians are responsible for teaching the patient that that's not the case."

More than 20 million Americans have type 2 diabetes. Obesity, age and lack of exercise all increase the risk for the disease, which is characterized by a progressive loss of insulin-producing beta cells. Diabetes is the single greatest independent risk factor for heart disease, as well as a contributor to a number of other medical problems, including blindness and kidney disease.

The standard initial treatment for type 2 diabetes is a single drug, often metformin, followed by the addition of more oral hypoglycemic agents as needed.

For this study, researchers evaluated the effectiveness of offering insulin-based therapy as an initial treatment option to newly diagnosed type 2 diabetes patients. They compared rates of compliance, satisfaction, effectiveness, safety and quality of life among the patients, who were randomized to receive either the standard triple oral therapy or insulin plus metformin, an oral drug that helps regulate blood sugar levels.

The patients, ranging in age from 21 to 70 years old, had been diagnosed with type 2 diabetes within the past two months. Researchers recruited study participants from Parkland Memorial Hospital or by self-referral to the Clinical Diabetes Research Clinic at UT Southwestern between November 2003 and June 2005.

After enrollment, every participant followed an insulin and metformin regimen for three months. The patients were then randomized to continue taking insulin and metformin or begin the triple oral therapy regimen. All participants were checked monthly for the first four months, at six months after randomization, and every three months thereafter for three years. Of the 58 patients randomized, 24 of the insulin-treated group and 21 of the triple oral therapy group completed the study.

The researchers found that the patients taking insulin plus metformin had fewer low-blood-sugar, or hypoglycemic, events, gained less weight and reported high satisfaction with the insulin.

Dr. Lingvay said she hopes physicians use these findings as the rationale to offer insulin-metformin as the first, rather than last, line of defense.

"Modern medicine uses insulin as a very effective and safe treatment tool," she said. "With the new devices that we're using, giving yourself an insulin shot is not much harder than taking pills."

The data represent the first three years of a six-year study still under way at UT Southwestern. The next step, Dr. Lingvay said, is to begin analyzing how the insulin plus metformin and oral triple therapy regimens affect insulin production in beta cells.

Other UT Southwestern researchers involved in the study included Jaime Legendre, recipient of a Clinical Research Fellowship from the Doris Duke Charitable Foundation; Dr. Polina Kaloyanova, former fellow in endocrinology; Dr. Song Zhang, assistant professor of clinical sciences; and Beverley Adams Huet, assistant professor of clinical sciences.

The study was supported by Novo Nordisk Inc., the National Institutes of Health and the Doris Duke Charitable Foundation.