Increased expression of a certain protein in the brain appears to halt the progression of Alzheimer’s disease, according to a study conducted by a team that includes Charles DeCarli, a professor of neurology and director of the UC Davis Alzheimer’s Disease Center. The findings, which appear in the current issue of The Journal of Neuroscience, could cause a dramatic change in the way scientists and researchers search for a therapy for the disease.
The protein that appears to stop the disease is called transthyretin.
“The results of our work demonstrate that if we can introduce molecules and drugs into the brain and increase transthyretin levels, we could slow the progression of Alzheimer’s pathology,” said DeCarli. The research team was led by Jeff Johnson, an associate professor in the School of Pharmacy at the University of Wisconsin. Johnson co-authored the report with Thor Stein, a former graduate student in the University of Wisconsin’s M.D./Ph.D. program.
Researchers have long searched for an animal model that mimics the pathology of Alzheimer’s disease to test potential therapies. Scientists have genetically engineered mice to express mutated genes from the families of patients with early-onset Alzheimer’s disease, producing several mouse lines that over-express the human amyloid precursor protein (APP), a protein involved in the development of the disease. Although the mice developed plaque formation in their brains, they did not develop the other hallmark of Alzheimer’s disease — neurofibrillary tangles, a leading sign that neural cells are dying. Most researchers viewed this as limitation to the model, but Johnson decided to find out why the mice had amyloid depositions and plaques, but neurons did not die and neurofibrillary tangles, another pathological feature of Alzheimer’s disease, did not form.
Johnson based his research on the widely held Amyloid hypothesis that states when the APP is cut into pieces in the human brain, there are “good” cuts and “bad” cuts. The “good” cuts are proteins that help to protect neurons, while the “bad” cuts are toxic beta-amyloid protein which, when present in large amounts, causes neural cell death, leading to cognitive function loss. In Alzheimer’s patients, “bad-cut” proteins significantly outnumber “good-cut” proteins. He hypothesized that there was something different about the brains of the mice that prevented further injury from the overexpressed APP.
To test this hypothesis, Johnson examined the gene expression patterns of protective proteins in the brains of the mice with plaque formation and found that the levels of a pair of specific proteins, transthyretin and IGF-2, increased dramatically. Because transthyretin had been shown in test tubes to bind to the toxic beta-amyloid protein, the researchers hypothesized that in the mice, the transthyretin was preventing the “bad-cut” toxic beta-amyloid protein from interacting with the neuronal cells, thereby preventing tangle formation and subsequent neuronal cell death.
When the researchers introduced an antibody into the mouse brain that prevented transthyretin from binding with beta-amyloid protein, the mice developed early signs of neurofibrillary tangles and increased neuronal cell death. The researchers have verified that the “good-cut” protein has similar protective effects in human brain tissue in vitro.
The next challenge for researchers is developing a reliable method to deliver transthyretin into the brain, or developing drugs that increase transthyretin expression in the brain to combat the neurotoxicity of beta-amyloid.
“These findings represent a great opportunity to identify a new concept that other researchers and drug companies can pursue,” said DeCarli. “This could trigger a new approach to Alzheimer’s disease treatment. Instead of treating the cognitive symptoms, we might be able to prevent the loss of neurons that result in those symptoms.”
DeCarli said there could be a time when family members with a genetic predisposition to Alzheimer’s disease could take a yet-undeveloped drug or molecule to increase transthyretin protein and prevent the disease from developing. It also could theoretically halt the disease progression in patients in the early stages of the pathology, preserving a higher level of cognitive function.
To see the full report, go to www.jneurosci.org.
