Colorado State University Researchers Discovers What Causes Brain to Shrink; Provides Key to Solving Mysteries of Preventing Dementia

Colorado State University researchers have discovered that low levels of two chemicals in the brain cause the brain to shrink — a condition that leads to dementia – and the discovery could help scientists prevent the condition. While researchers have suspected that both insulin and insulin-like growth factors may play an important role in dementia, this new research shows for the first time that the two chemicals work together to prevent the brain from shrinking and that low levels are the cause of cell loss and eventual dementia.

“This research provides us with hope for the first time that scientists can find a way to actually prevent the progression of dementia in people with conditions such as Alzheimer’s, diabetes and Parkinson’s disease,” said Douglas Ishii, a professor in the Department of Biomedical Sciences and a leading researcher in the discovery. Ishii points out that this discovery is in initial stages, and other research including clinical trials should be conducted to find ways to test and apply the findings.

Before this discovery, researchers did not understand what causes the brain to progressively shrink. That missing information made it impossible for the medical field to develop interventions that significantly slowed, stopped or reversed conditions such as Alzheimer’s.

Current treatments for dementia related to diseases such as Alzheimer’s include multiple drugs that work only temporarily to delay the progression of symptoms while the brain continues to shrink. In part, these treatments aren’t a permanent solution because of the body’s inability to transfer insulin and insulin-like growth factors from the blood into the brain, called the blood-brain barrier. For example, a person with Alzheimer’s or diabetes may have high levels of insulin in his blood, but the insulin in the brain is abnormally low because of a blockage between the blood and brain. Scientists haven’t yet discovered a way to cross that barrier with medications.

Insulin-like growth factors are proteins that support nerve cell survival, the regeneration of nerves and the formation of synapses, which is the connection between nerve cells. The protein is often reduced in diabetic and Alzheimer’s patients; insulin levels also are low. Ishii discovered 25 years ago that insulin-like growth factors can prevent diabetes related peripheral nerve damage. For many years, scientists have been working to understand the relationship between diabetes and dementia; 80 percent of Alzheimer’s patients have a history of diabetes or pre-diabetes. Diabetic people also are at a higher risk of developing dementia.

Previous research from Harvard has shown that low insulin receptor levels in the brain neurons weren’t related to brain shrinkage, and Ishii’s previous research, conduced with the assistance of graduate students, has also shown that increasing only insulin-like growth factor levels does not prevent brain shrinkage.

The recent discovery points to the gradual loss of both insulin and insulin-like growth factors with aging and disease likely increases the risk for brain shrinkage.

“Insulin and insulin-like growth factor levels in the brain progressively go downhill with aging and in Alzheimer’s patients, most likely due to insulin resistance,” said Ishii. “Eventually, brain cells start to die. We believe, based on our findings, that with appropriate treatment with these two proteins we may be able to bring these essential brain proteins back to normal levels. For the first time, it may be possible to develop a treatment that prevents brain atrophy and prevents the progression of dementia.”

Ishii’s study showed that in research models, brain shrinkage, brain cell loss, protein loss and damage to neurons and glia cells, which are cells that provide support and nutrition to the brain, were virtually halted in brain tissue when insulin and insulin-like growth factors were put directly into the brain tissue.

Alzheimer’s is the most prevalent form of dementia and it impacts about 36 million people world-wide.

Ishii’s research team on the project included graduate student Predrag “Pete” Serbedzija and Jim Madl, also a researcher in the biomedical sciences department. The research discovery is based on many years of research support from the National Institute of Neurological Diseases and Stroke, Centers for Disease Control and Prevention, and Colorado Commission on Higher Education. The study is appearing in the next issue of Brain Research.

The Department of Biomedical Sciences is part of the College of Veterinary Medicine and Biomedical Sciences.