Researchers at the University of Wisconsin-Madison have shed light on an innovative way to treat patients with Alzheimer’s disease.
The researchers found the expression of a protein called transthyretin may prevent or significantly halt the disease. The findings appeared in last week’s 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 disease,” said UW Associate Professor Jeff Johnson, the leader of the research group.
Alzheimer’s, the leading cause of dementia, affects nearly 4.5 million Americans, according to the Alzheimer’s Association. It is characterized by clumps, called amyloid plaques, and tangled bundles of fibers, called neurofibrillary tangles, which lead to the neuron cell death that causes the loss of brain function associated with the disease.
For years, researchers sought an animal model for Alzheimer’s disease to find treatments for humans. They took genetically modified mice that expressed the mutated gene from early-onset Alzheimer’s patients and made them over-express human amyloid precursor (APP), a protein associated with the development of the disease.
“We hypothesized that, if given the gene for the amyloid precursor, the mice would also develop Alzheimer’s, but we were surprised to see that somehow these mice dealt with the amyloid plaques and didn’t get Alzheimer’s disease,” Johnson said.
In humans, accumulation of a toxic beta-amyloid protein leads to massive neural cell death. But the toxic protein did not accumulate in these mice.
Johnson said the transgenic mice dramatically over-expressed transthyretin, a secreted protein typically found in low levels of cerebral spinal fluid, by more than 30-fold. This suggested that the protein might be involved in the development of Alzheimer’s in humans.
While most researchers continued to pursue the development of an animal model for Alzheimer’s disease in the mice by attempting to induce neuron cell death, Johnson and his team chased the mechanism by which mice survive the disease.
Johnson and researchers who analyzed the brains of the mice that did not develop Alzheimer’s disease hypothesized that transthyretin was binding to the toxic beta-amyloid precursor protein, thus blocking it from forming the typical tangles and neuron cell death seen in Alzheimer’s patients.
A further experiment supported their hypothesis. When the researchers injected an antibody into the brain of the mice to halt the binding of transthyretin to the neurotoxin beta-amyloid protein, the mice developed neurofibrillary tangles and had increased neuron cell death that led to Alzheimer’s. The researchers concluded that transthyretin must have a protective effect on the brain.
“This gives us researchers a complete twist in the philosophy for how we’ve been treating Alzheimer’s,” Johnson said. “Instead of treating the cognitive symptoms, we can actually prevent the loss of the neurons that result in the cognitive symptoms.”
Johnson said that transthyretin has already proven effective in human brain tissue samples and that similar protective effects may be seen in human patients.
Now researchers must find ways to mimic the effect in humans to apply the information to pharmaceutical development. A potential new drug could increase the transthyretin protein to battle the neurotoxic beta-amyloid. Scientists believe that this could halt the progression of Alzheimer’s in early-onset patients and might also prevent the disease from developing in individuals who have a genetic predisposition to the disease.
The Wisconsin Alzheimer’s Institute is preparing to test the potential drugs on human patients so individuals can receive the new treatment quickly.
“I believe this is a very important piece of work, and it quite possibly may lead to a completely new line of treatment for Alzheimer’s patients,” said Mark A. Sager, UW associate professor of medicine and director of the Wisconsin Alzheimer’s Institute. “The potential of this research is phenomenal.”
The Alzheimer’s Association Memory Walk, a six-mile fundraiser, will take place Sept. 18 in Madison, according to the association’s website.
