Stimulation of a receptor in the brain that controls insulin responses has been shown to halt or diminish the neurodegeneration of Alzheimer's disease, providing evidence that the disease can be treated in its early stages, according to a study by researchers at Rhode Island Hospital and Brown Medical School.
Researchers have found that peroxisome-proliferator activated receptor (PPAR) agonists prevent several components of neurodegeneration and preserve learning and memory in rats with induced Alzheimer's disease (AD). They found that an agonist for PPAR delta, a receptor that is abundant in the brain, had the most overall benefit.
"This raises the possibility that you can treat patients with mild cognitive impairment who have possible or probable Alzheimer's disease. This is really amazing because right now, there's just no treatment that works," says lead author Suzanne M. de la Monte, MD, MPH, a neuropathologist at Rhode Island Hospital and a professor of pathology and clinical neuroscience at Brown Medical School in Providence, RI.
The study appears in the September issue (Volume 10, Issue 1) of the Journal of Alzheimer's Disease (http://www.j-alz.com).
In previous studies, the researchers demonstrated that Alzheimer's is a brain-specific neuroendocrine disorder, or a Type 3 diabetes, distinct from other types of diabetes. They showed that insulin and IGF-I receptors are produced separately in the brain, and begin to disappear early in Alzheimer's and continue to decline as the disease progresses. As insulin signaling breaks down, it leads to increased oxidative stress, impaired metabolism and cell death -- all causing neurodegeneration.
Scientists were also previously able to replicate Alzheimer's in rats with Streptozotocin (STZ), a compound that is known to destroy insulin producing cells in the pancreas and cause diabetes. When injected into the brains of rats, the compound mimicked the neurodegeneration of Alzheimer's disease -- plaque deposits, neurofibrillary tangles, diminished brain size, impaired cognitive function, cell loss and overall brain deterioration.
Having created an animal model for Alzheimer's, researchers in this study induced Alzheimer's with STZ and then administered treatment with three classes of PPAR agonists -- alpha, gamma and delta. All are found in various tissues and organs in the body, including the brain, and PPAR gamma is already FDA approved as a treatment for Type 2 diabetes, or adult-onset diabetes. The two other classes of PPAR agonists have not yet been approved for clinical use.
Following treatment, many of the abnormalities associated with Alzheimer's were reduced or nearly disappeared. The agonists affected different regions of the brain, with PPAR delta producing the most striking effect in preserving the hypothalamus and temporal lobes, areas of the brain responsible for memory, learning, and behavior. In these brain regions, PPAR alpha and PPAR gamma were effective in reducing amyloid gene expression. PPAR delta had the most benefit for reducing oxidative stress and improving learning and memory.
"That was the most spectacular," de la Monte says, "because everybody wants something for cognitive impairment, and that was the most improved with the PPAR delta agonist."
Researchers were not able to stop the deterioration of insulin and its receptors. However, by administering PPAR, they were able to bypass the defects in insulin signaling and preserve the cells that need insulin to thrive. PPAR molecules go directly to the nucleus of cells and tell DNA to turn on or off genes that are normally regulated by insulin, thus preventing them from dying and allowing them to communicate with each other. The major effects of the PPAR treatments were to increase brain size, preserve insulin and IGF-II receptor bearing neurons, and preserve learning and memory.
"The trigger for dementia is the loss of insulin and IGF producing cells. The cells that need those growth factors subsequently die. This study shows you can block the second phase, which is responsible for dementia. This is great news for patients since you treat early stages of disease," de la Monte says.
Another promising result for Alzheimer's patients is that these drugs could be given in the form of a pill, de la Monte says. In the study, the drugs were injected to control the amounts administered.
"One of the most exciting findings was that peripheral (intraperitoneal) injection of the PPAR agonists either partially or completely rescued the brains from neurodegeneration," the authors write.
Alzheimer's appears to be caused by parallel abnormalities -- impaired insulin signaling and oxidative stress, which is regulated by the genes NOS and NOX. The PPAR agonists treatments target both problems. They preserve the cells regulated by insulin and IGF, and they decrease oxidative stress, resulting in fewer lesions in the brain.
"If the diagnosis is suspected or patients are in the early phases of AD, there's a good possibility they could get treatment that will help them. It's possible that in the moderate phase, treatment will also help, but more work needs to be done to show that," de la Monte says.
Treatment is not likely to work in the late stages of the disease, she says, because the cells have already died.
Other authors on the paper are: Ming Tong, Nataniel Lester-Coll, Michael Plater Jr. and Jack R. Wands, all of Rhode Island Hospital and Brown Medical School.
This study, through the Liver Research Center at Rhode Island Hospital and Brown Medical School, was supported by grants from the National Institutes of Health.
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