The chemistry of memory: New strategies for battling brain disease
It has taken more than a decade for Regina Murphy and her colleagues to determine that sometimes it’s actually better to rush things.
At least that’s the case when those things are protein processes in the brain that can lead to devastating neurological diseases like Alzheimer’s and Huntington’s.
Murphy, the Smith-Bascom Professor of Chemical and Biological Engineering, is studying the kinetics of proteins and peptides that aggregate in the brain. Her work has helped to dramatically change the research paradigms that guide neurological drug development, creating new possibilities for therapies that could treat not only the symptoms of these diseases, but perhaps the actual causes.
Alzheimer’s, the most common form of dementia, is a progressive and fatal brain disease that currently has no cure. Characterized by severe memory loss and confusion, the disease affects as many as 5.3 million people in the United States, according to the Alzheimer’s Association. A new patient develops the disease every 70 seconds, and while the majority of patients are over age 65, as many as 200,000 people in their 30s, 40s and 50s are living with the disease.
Doctors do not fully understand the cause of Alzheimer’s, though age, family history, and serious head injuries appear to be risk factors. Similarly, scientists do not know exactly what causes Alzheimer’s at the cellular level, but they have linked the disease to a particular protein in the brain.
Imagine the protein, called the beta amyloid precursor protein (APP), as a chain. A few links of this chain make up an amino acid called beta amyloid. Enzymes work like a saw to “cut out” the beta amyloid section from the rest of the protein. When cut pieces of beta amyloid find each other, they bind into links called oligomers. These oligomers, or intermediates, grow as they find more and more beta amyloid copies, eventually forming a clump called a fibril that can measure around 1 micron long, which is visible in the brain tissue.
Rethinking the disease process
Patients with Alzheimer’s have these beta amyloid fibrils, and for years, researchers and drug companies assumed that the fibrils were causing cell death and disease. However, in the late 1990s, Murphy and UW-Madison Chemistry Professor Laura Kiessling showed that in the case of Alzheimer’s disease, the fibrils themselves aren’t the problem. Rather oligomer “clumping” is the toxic part of the process. And, speeding up this intermediate aggregation into fully formed fibrils actually reduces overall toxicity in the brain.
Murphy, who has been a member of the UW-Madison faculty for more than 20 years, recalls visits to pharmaceutical companies where she met researchers trying to develop drugs intended to prevent fibrils from forming. “They weren’t looking at whether they were just pushing everything back to the intermediate phase, which would have been worse since that’s the most toxic stage, because it just wasn’t accepted wisdom that the intermediates were bad,” she says.
Murphy believes beta amyloid is still the main culprit in Alzheimer’s since the intermediates appear to have a physical effect on the cell membrane of neurons, which is where the cell most actively transmits and receives signals. Neurons make up around 10 percent of all brain cells and are, says Murphy, the racehorses of our bodies. “They’re fast and great, but they’re touchy,” she says, adding that neurons appear to be particularly sensitive to changes in their physical properties, resulting in cell death.
While some scientists have yet to believe that fibrils are not “bad actors” in and of themselves, the Alzheimer’s research community has experienced what Murphy describes as a “sea change in how we think about the whole problem with these proteins.” The new emphasis on beta amyloid intermediates has led to research into alternatives to therapies that prevent or target the fully formed fibrils.
Turning humans into mice
One alternative Murphy is studying in collaboration with UW-Madison Pharmacy Professor Jeffrey Johnson is another protein in the brain that could be used to protect neural cells from beta amyloid — and perhaps even prevent the onset of Alzheimer’s disease.
In 2002, Johnson’s lab published the results of experiments that injected mice with mutated forms of human APP. As in humans, the transgenic mice produced the damaging beta amyloid deposits in their brain tissues. Unlike in humans, the mice did not develop other signs of Alzheimer’s, such as neurofibrillary tangles (aggregates of a different protein inside neurons) that lead to cell death. Instead, the mice produced an excess amount of another protein, called transthyretin (TTR), which appears to interact with beta amyloid and reduce its toxicity.
Murphy and Johnson have received almost $413,000 in federal stimulus funding from the National Institutes of Health to study how exactly TTR affects beta amyloid and how researchers can induce this interaction to perhaps prevent Alzheimer’s from ever developing in brain tissue. “We want to find out how to turn a human into a mouse, basically,” Johnson says.
While the experimental mice produced more TTR, human patients with Alzheimer’s have decreased levels of the protein. High levels of TTR can either force — or totally prevent — aggregation of beta amyloid. While Murphy and Johnson don’t understand fully why this happens, they are working on strategies to increase TTR levels to learn more.
Their many research questions include whether they can develop small molecules that can facilitate TTR and beta amyloid interaction and how much they should increase TTR levels to reduce beta amyloid toxicity. The answers to these questions could lead to the development of drug therapies to treat the actual Alzheimer’s disease process, instead of only alleviating symptoms.
This highly innovative Alzheimer’s disease research is likely to lead to an effective therapy for the disease, says sanjay Asthana, the UW-Madison Duncan G. and Lottie H. Ballantine Chair in Geriatrics and director of the Wisconsin Alzheimer’s Institute and Wisconsin Comprehensive Memory Program. “Such a therapy will favorably alter the basic pathology of Alzheimer’s, which could potentially slow the progression of the disease and, hopefully, one day prevent the disease from developing,” he says.
In research that has the potential to make such a significant difference, Johnson says collaboration is key. “Combining expertise with those outside of your area is going to be the nature of science in the future,” he says. “We have to cross those disciplinary bridges in order to move forward faster than we have been. The whole of our research is going to be greater than the sum of our individual parts.”
Going beyond Alzheimer’s
In addition to her work with Johnson, Murphy has received almost $300,000 from the National Science Foundation to study protein folding and aggregation in a set of rare neurological diseases, such as Huntington’s disease. The Huntington’s Disease Society of America estimates more than 250,000 people in the United States have it or have a significant risk of inheriting the devastating genetic brain disease, which gradually shuts down the neurons that control muscles and eventually destroys cognitive abilities as well.
Like Alzheimer’s disease, Huntington’s and related diseases are caused by sections of proteins in the brain that misbehave. The specific proteins and amino acids at work are different — the protein is huntingtin and the amino acid is glutamine — but despite the distinct challenges in her separate lines of research, Murphy approaches all of the proteins she studies like a chemist would approach any molecule or polymer. “These are biological problems, but some basic physical chemistry comes into play,” she says. “I think this perspective allows me to bring a different dimension than a classically trained biochemist brings to these questions.”
Ultimately, Murphy is driven by the fact that the basic behaviors of proteins have a direct, widespread effect on human health. “We’re dealing with the fundamental physical chemistry of how these proteins — these molecules — behave, and why,” she says. “And the biological consequences of these behaviors — disease — give us reasons to investigate beyond pure curiosity.”