Ashe Lab Aims to Halt, Potentially Reverse Memory Loss Associated with Dementia

Karen Ashe, MD, PhD

Nearly 50 million people suffer from dementia worldwide, and for patients, families and friends, the disease often has a devastating physical, psychological, social and economic impact. Karen Ashe, MD, PhD, a professor in the Department of Neurology at the University of Minnesota Medical School, has been leading research aimed at better understanding how and why dementia develops along with how it might be treated.

Through the N. Bud Grossman Center for Memory Research and Care, the Ashe Lab collaborates with five additional labs and a multidisciplinary 20-person team to advance memory research. The Ashe Lab is currently working to translate research findings into a drug that could halt or potentially reverse memory loss associated with different forms of dementia.

“This is a multidisciplinary effort to develop an oral drug that will penetrate the brain and safely inhibit an enzyme called caspase-2,” Dr. Ashe said. “We want to inhibit caspase-2 because we’ve discovered that it’s abnormally activated in several neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, frontotemporal dementia and Lewy body dementia, which is related to Parkinson’s disease.”

Since the process occurs across the spectrum of dementia, the drug would effectively treat 90% of its forms. In a groundbreaking 2016 paper published in Nature Medicine, she and her team discovered that overactivation of caspase-2 causes overaccumulation of a neuronal protein called tau, in a part of the neuron responsible for receiving neurotransmissions from other neurons. This overaccumulation of tau weakens the synaptic connection between neurons and can accelerate memory loss.

“This weakening is likely part of a normal process to help us forget things that we don’t need to remember,” Dr. Ashe said. “However, when it’s abnormally activated, we forget things that we really need to remember.”

Treatments of the Future

The lab aims to create a treatment that dampens excessive caspase-2 activity but doesn’t block it entirely. 

“You could end up retaining too much information, which would also interfere with normal learning and memory,” Dr. Ashe explained.

The team has developed a compound that is both the most selective and potent caspase-2 inhibitor known in the research world. This compound was prepared by Gurpreet Singh, PhD, a medicinal chemist in the Institute for Therapeutics Discovery and Development.

“We know that it works very well in improving and strengthening synaptic connections,” Dr. Ashe said. “We are very excited moving this forward to try to find a compound that can be turned into a pill and is capable of crossing the blood-brain barrier.”

The pill would normalize the synaptic strength that’s been abnormally weakened in the disease process, but in order for the medication to work, the synaptic connections would need to be present. Earlier in the disease diagnosis, many of these synapses still exist but in a weakened state.

“We believe the drug that we eventually develop will strengthen the synaptic connections and enable people to not forget as much and have more normal memory,” Dr. Ashe said. 

For many individuals, the process of developing dementia might begin 10 to 20 years before an official diagnosis, and the person may or may not recognize symptoms. It’s also impossible to predict whether someone will develop Alzheimer’s or some other form of dementia at that stage.

“If this pill works, it would be possible to treat people who have subjective memory loss, who might not feel ‘as sharp as they once were,’” Dr. Ashe said. “However, I think that would have to be accompanied by some testing to ensure their caspase-2 activity is actually abnormally elevated, otherwise there would be no reason to believe it would work.”

Ingredients for Success

While it’s unclear what exactly triggers abnormal development of caspase-2, it may be linked to oxidative stress, an imbalance of free radicals and antioxidants in the body, which can cause cells to become transformed and cause aging.

“Scientists have found that over time, atoms like oxygen are abnormally added to different proteins and DNA, and this results in a loss of function and caspase-2 activation,” Dr. Ashe said. “Caspase-2 is also activated when DNA is damaged or when abnormal proteins accumulate in the brain, both processes which occur in neurodegenerative disorders.” 

Dr. Ashe added that maintaining good cardiovascular health is believed to be helpful in the prevention of Alzheimer’s disease, including control of blood pressure, diabetes and cholesterol. Still, there’s currently no guaranteed prevention or treatment option. While Dr. Ashe’s work bringing a medication to treat dementia from the lab to the clinic is estimated to take at least 10 years, the ingredients to achieving this feat are there.

“We have some extraordinarily committed and talented scientists, the most important ingredient,” Dr. Ashe said. “Federal funding is also a key ingredient. It’s going to involve continued funding support from the University of Minnesota and the federal government, especially the National Institutes of Health (NIH), and philanthropists, forms of funding we are fortunate to enjoy. Another essential ingredient will come from industry, which has the know-how and resources to take a compound and get it approved by the FDA.”

The N. Bud Grossman Center for Memory Research and Care includes faculty from the U of M College of Science and Engineering, the Medical School, the College of Pharmacy and the School of Public Health, who are working together to develop a center for clinical and translational Alzheimer’s disease research. 

“The center would enable researchers at the University of Minnesota to have better access to patients for clinical trials, fluid specimens and imaging studies,” Dr. Ashe said. “We need the diversity of expertise represented in different colleges and schools to make this happen, and it’s going very well.”

The center would aid clinical research and extend strengths in the basic sciences to advance innovations that improve patient outcomes. Dr. Ashe hopes that the foundation of this center can be established within the next two to three years, and in conjunction with her lab’s research, there’s tremendous potential to positively impact the lives of Minnesotans and beyond.

“We could transform patient care,” Dr. Ashe said. “This compound – a caspase-2 inhibitor – would repair the damaged synapses so that patients would literally improve, not just experience a slowing of the disease.”

June is Alzheimer’s and Brain Awareness Month. Learn about making a gift to support Alzheimer’s research through the N. Bud Grossman Center for Memory Research and Care.

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