Aaron Conklin, Wisconsin Week
In a finding that may cause a dramatic shift in the way scientists and researchers search for a therapy for Alzheimer’s disease, a team of researchers led by Jeff Johnson, an associate professor at the School of Pharmacy, has discovered that increased expression of a protein called transthyretin in the brain appears to halt the progression of the disease. The findings appear in the current issue of The Journal of Neuroscience.
“This work shows convincingly that if we can intervene in Alzheimer’s pathology by introducing molecules and drugs into the brain and increase transthyretin levels, we could slow the progression of the pathology,” says Johnson, who co-authored the report with Thor Stein, a former graduate student in UW’s M.D./Ph.D. program who performed most of the experiments. “Even if patients have plaque formation in the brain, they still could have normal function.”
For years, researchers have focused on creating an animal model that mimics the pathology of Alzheimer’s disease to test potential therapies. By genetically engineering mice to express mutated genes from the families of patients with early-onset Alzheimer’s disease, researchers produced several mouse lines that over-express the human amyloid precursor protein (APP), a protein involved in the disease development. While the mice developed plaque formation in their brains, they didn’t develop the other hallmark of Alzheimer’s disease — neurofibrillary tangles, a leading indication that neural cells are dead or dying.
Most researchers noticed this and continued to search for a way to create the perfect mouse model. Johnson had a different thought.
“I said to myself, everybody is trying to kill neurons in mice to create the Alzheimer’s pathology,” he explains. “And here we have a mouse that has amyloid deposition and plaques yet no neurons are dying. Let’s try to figure out why these mice aren’t getting the disease.”
The answer was surprising, and could completely alter the way researchers think about treating Alzheimer’s disease.
Johnson’s research is based on the widely held amyloid hypothesis: When amyloid precursor protein (APP) is cut into pieces in the human brain, there are “good” cuts – proteins that help to protect neurons – and “bad” cuts, toxic beta-amyloid protein that, when present in large amounts, causes massive neural cell death, leading to cognitive function loss. In Alzheimer’s patients, “bad-cut” proteins significantly outnumber “good cut” proteins.
Stein, under Johnson’s supervision, analyzed the brains of the mice with plaque formation, and noticed something interesting: The levels of a pair of specific proteins, transthyretin and IGF-2, increased dramatically. Since transthyretin had been shown in test tubes to bind to the toxic beta-amyloid protein, Johnson and Stein hypothesized that in the mice, the transthyretin was preventing the “bad cut” toxic beta-amlyoid protein from interacting with the neuronal cells, thereby preventing tangle formation and subsequent neuronal cell death.
“Somehow, the adapted mechanism in the mice was due to the balance between the good cut and the bad cut,” says Johnson. “The good cut product was causing the increase in transthyretin, which was balancing the toxicity of the beta-amyloid, or bad-cut protein.”
Further experimentation bore out their theory. When Stein 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. Johnson and Stein verified that this “good” cut product has similar protective effects in human brain tissue in vitro. The latter finding is particularly significant.
“If we couldn’t show that, we wouldn’t have known if this protective mechanism is as relevant to humans as it was to mice,” Johnson explains.
The next question – and it’s a big one – involves 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.
“This gives us a great opportunity to identify a new concept in the field that other people and drug companies will pick up on,” says Johnson. “Hopefully this will spur a new approach to Alzheimer’s disease. Instead of treating the cognitive symptoms, we can actually prevent the loss of the neurons that result in the cognitive symptoms.”
Johnson foresees 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 could also theoretically halt the progression of the disease in patients in the early stages of the pathology, preserving a higher level of cognitive function.
The Wisconsin Alumni Research Foundation (WARF) has filed a U.S. patent application on behalf of the chool of Pharmacy on specific protein sequences that confer this protective effect. In the coming months, WARF hopes to begin licensing this technology to drug companies that can begin researching an effective delivery method.
Johnson and Stein believe that these new discoveries may eventually be combined with other therapies to help prevent the progression of Alzheimer’s disease.
“What makes this interesting and novel is that nobody has really identified this mechanism for potential therapeutics,” Johnson says. “I believe there will be drugs that cross the blood-brain barrier that can be used for Alzheimer’s therapy. We’ll find those molecules. They may already be out there, but nobody has looked at them in this context.”
Johnson and Stein’s research was and continues to be funded by the National Institute of Environmental Health Sciences. To view the report in full, visit www.jneurosci.org