Researchers at Rhode Island Hospital and Brown Medical School have discovered that insulin and its receptors drop significantly in the brain during the early stages of Alzheimer's disease, and that levels decline progressively as the disease becomes more severe, leading to further evidence that Alzheimer's is a new type of diabetes. They also found that acetylcholine deficiency, a hallmark of the disease, is linked directly to the loss of insulin and insulin-like growth factor function in the brain.
The study, published in the November issue of the Journal of Alzheimer's Disease (http://www.j-alz.com), is the first to look at insulin levels early in the course of the disease. The authors' previous work published earlier this year primarily focused on the late stages of Alzheimer's.
"Insulin disappears early and dramatically in Alzheimer's disease. And many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signaling. This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes," says senior author Suzanne M. de la Monte, a neuropathologist at Rhode Island Hospital and a professor of pathology at Brown Medical School in Providence, RI.
The study analyzed postmortem brain tissue of 45 patients with a diagnosis of either normal aging or different degrees of Alzheimer's neurodegeneration, termed "Braak Stages." Researchers analyzed insulin and insulin receptor function in the frontal cortex, a major area affected by Alzheimer's. They found that with increasing severity of the disease, levels of insulin receptors and the brain's ability to respond to insulin decreased markedly.
"In the most advanced stage of Alzheimer's, insulin receptors were nearly 80 percent lower than in a normal brain," de la Monte says.
Researchers found two parallel abnormalities related to insulin in Alzheimer's. First, insulin levels decline as the disease progresses. Second, insulin and its related protein IGF-I lose their ability to bind to corresponding cell receptors, creating a resistance to the growth factors and thus causing cells to malfunction and eventually die.
"This has important implications for treatment," de la Monte says. "If you could target the disease early, you could prevent the further loss of neurons. But you would have to target not just the loss of insulin but the resistance of its receptors in the brain."
Researchers also offer an explanation for the acetylcholine deficiency that is linked to dementia and has long been recognized as an early abnormality in Alzheimer's. They found that insulin and IGF-I stimulate the expression of choline acetyltransferase (ChAT), the enzyme responsible for making acetylcholine. This discovery shows a direct link between insulin and IGF-I deficiency and dementia.
"We're able to show that insulin impairment happens early in the disease. We're able to show it's linked to major neurotransmitters responsible for cognition. We're able to show it's linked to poor energy metabolism, and it's linked to abnormalities that contribute to the tangles characteristic of advanced Alzheimer's disease. This work ties several concepts together, and demonstrates that Alzheimer's disease is quite possibly a Type 3 diabetes," de la Monte says.
Earlier this year, de la Monte and co-authors provided the first evidence that insulin and its related proteins are produced in the brain and that reduced levels of both are linked to the late stages of Alzheimer's. They surmised that Alzheimer's is a complex neuroendocrine disease that originates in the central nervous system, raising the possibility of a new type of diabetes.
This study was supported by grants from the National Institute of Alcoholism and Alcohol Abuse, the National Institutes of Health and the Bryan Alzheimer's Disease Research Center.
Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of Brown Medical School. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks 13th among independent hospitals who receive funding from the National Institutes of Health, with research awards of more than $27 million annually. Many of its physicians are recognized as leaders in their respective fields of oncology, cardiology, orthopedics and minimally invasive surgery. The hospital's pediatrics wing, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery.
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