Author: gcmrc

“Research is sort of like a baseball game. Not much happens for a while and then someone hits a homerun.”
~Karen Hsiao Ashe, MD, PhD, Founding Director, N. Bud Grossman Center for Memory Research and Care

The N. Bud Grossman Center for Memory Research and Care continually aims to expand high-impact research that moves the needle toward an eventual cure. The Ashe Lab team examines key proteins and processes that they believe underlie Alzheimer’s, while building research partnerships to expedite mouse models and drug development. These collaborations are paving the way for effective treatment and prevention strategies in humans.

Initial Research Question: Are neurofibrillary tangles the cause of Alzheimer’s disease and neurodegeneration?
Answer: No. Over the last decade, Karen Ashe and her team have found that tangles are not the cause of Alzheimer’s, but rather a sign of the disease. Tau* is likely a culprit. Today, the main focus of the Ashe lab’s research is developing a drug to stop the damage caused by tau*.

 

Stopping Tau*

“With the tau project, we’re able to reverse existing problems in mice. So we might be able to take someone who’s beginning to lose their memory, give them something, and have their memory function return to normal.”
~Karen Hsiao Ashe, MD, PhD

In 2016, Karen Ashe and her research team had their most productive year yet in terms of understanding the role of tau* in Alzheimer’s, and finding ways to prevent its impact. This work was launched years ago by donor and National Institutes of Health support and it was recently published in Nature Medicine (see below). This research path shows immense promise and Dr. Ashe recently decided to dedicate the remainder of her research career to developing a tau* drug and devising a test to measure tau* in people.

Over the past year, Ashe and her team have made a significant discovery about how tau* triggers neurodegeneration. They found that after being formed by an enzyme called caspase 2, tau* causes other forms of tau to infiltrate the dendritic spines (or antennae) of neurons and prevents them from carrying out effective communication.

Before taking a new position in Maryland, Dr. Xiaohui Zhao led this tau project to a successful conclusion (see Nature publication below). Of Xiaohui’s tremendous work, Dr. Ashe said, His command of experimental design and technique, leadership, and dedication were second to none. There is no doubt that he was the MVP in this epic project. 

Ashe’s team is now working to identify compounds that protect and restore communication between neurons by preventing tau* from forming. They have built partnerships with colleagues from the University, private donors, and a major pharmaceutical company to achieve this goal. With the help of Dr. Michael Walters and his team at the Institute for Therapeutics Discovery and Development (ITDD), they are now screening these chemicals to determine if any of them block the enzyme that generates tau*. Their next big steps will involve testing the most promising compounds in animal models and potentially moving these compounds to human clinical trials.

 

New Ashe Lab publication in Nature Medicine

Ashe Lab researchers identified a potential target for treating Alzheimer’s disease, which reversed memory loss in mice. This research marks a significant step forward in the fight against Alzheimer’s disease and memory loss. The research is published in the current issue of Nature Medicine.

 

 

MINNEAPOLIS/ST. PAUL (October 10, 2016) – University of Minnesota Medical School researchers identified a potential target for treating Alzheimer’s disease, which reversed memory loss in mice. The study could translate to new treatments and provides insight into what may be causing the disease.

Read more

As I contemplated the contents of this essay I realized my interest in medicinal chemistry actually started 40 years ago when I was in high school. My initial forays into this field included an ill-fated attempt to prepare the local anesthetic ethyl chloride in my parents’ garage. I am not really sure they completely understood what I was doing. The place must have smelled like a distillery since the first step of the synthesis was the production of ethanol by yeast. How I expected to isolate the ethylene gas required as the reactive intermediate in my planned synthesis is a mystery to this day. Suffice it to say, my project was put on hold when I found that I could only purchase concentrated sulfuric acid in tanker car volumes.

Ironically, my initial career goals were to be a Spanish-speaking lawyer in New York. However, my 10^th grade schedule wouldn’t allow for Spanish I, so I took chemistry instead. The rest, as they say, is history. I also built a gas chromatograph in high school and carried a slide rule on my belt…so I didn’t have many friends. I never studied Spanish or law. So much for childhood dreams, but I think things have turned out pretty well.

I am now proud to say that the experience garnered in these rougher years and the intervening four decades has finally paid off! I believe I now possess a rare combination of “academic” enthusiasm and medicinal chemist cynicism that makes me perfectly fit for my work in the ITDD (The Institute for Therapeutics Discovery and Development).

If you will pardon a dog-like metaphor, academics are typically like enthusiastically-herding border collies (this is most assuredly meant as a compliment) whilst medicinal chemists (at least the industrial types I know) are more like Dobermans with their jaws around your calf. My crossbred nature, nurtured by stints in the ivory tower (Dartmouth College) and the halls of medicine (Parke-Davis and Pfizer), turns out to be ideal for my current role as an innovation forager. In the ITDD I work at the interface of academic dreams and translational reality on a daily basis. To be ultimately effective I need to engage the dreams, seek out the truth, and then attempt to nurture the dream while injecting a dose of reality into the process. The evanescent, cloud-like ideas of great science may not be easily condensed into effective restoratives, but that’s my job…and I love it! I have had the chance to work on projects ranging from to Alzheimer’s disease and ataxias to anti-fungals and suppressors of suppressors, the latter being a new anti-tumor vaccine adjuvant discovery project. Where else would I get an opportunity like this?

My association with the Grossman Center for Memory Research and Care began back in 2007 when I met with Karen Ashe and Kathy Zahs on an interview trip in the Phillips-Wangensteen Building warren. They were both soo excited to talk with a medicinal chemist who might help decipher the interactions of Abeta56* with NMDA receptors that I left their company determined to work with them when I started my position at the UMN. While there are passionate researchers in industry, my experience is that none of them possess the passion for their work that many of the colleagues I work with in the academy. Decades of research focused on the same field is the difference, I suspect. Over the years of my collaboration with the GCMRC I have learned a bit about the biology of Alzheimer’s disease and have been able to contribute, in my own small ways, to the execution of projects related to AD drug discovery. I consider this a privilege. It is satisfying that I can apply my skills and the skills of my coworkers to such a potentially impactful project. Unfortunately, many AD biology researchers want for a translational institute like the ITDD. Their discoveries frequently languish in the valley-of-death between idea and utility because they don’t have the support needed to prepare proof-of-concept compounds. The biological and clinical expertise of the Grossman Center is a perfect match for the medicinal chemistry and other early stage drug discovery skills available at the ITDD. I am happy to be part of this match! And now I think I have plenty of friends!

“You treat a disease, you win, you lose. You treat a person, I guarantee you, you’ll win, no matter what the outcome.”  ~Patch Adams

For the more than 5 million Americans living with Alzheimer’s disease (AD) today, health care remains fragmented and poorly organized. Their 15 million caregivers—largely managing care at home—have no formally recognized or supported role in the health care system. Unlike other complex diseases with high care delivery demands (e.g. diabetes, heart failure), there is no widely accepted standard of care for dementia. This is highly problematic because health systems rely on such evidence-based standards to determine how clinical issues are prioritized, programs are funded, individuals are cared for, and how to engage both internal and external partners and communities. This shortfall, and the gap between actual health care practice and desirable outcomes for patients with dementia and their caregivers, highlights enormous need and opportunity. We are using this opportunity to engage in collaborative problem solving partnerships with stakeholder groups through the Twin Cities Consortium for Alzheimer’s Research (T-CAR).

T-CAR just wrapped up a six-month strategic planning process, and we more fully understand the unique role we can play in helping to effectively shape dementia ‘health care’ research in the community.  As a result of our strategic planning, T-CAR will focus its efforts on a few critical projects over the next 12 months. Our biggest project will be to develop a dementia health services research agenda, in partnership with existing T-CAR members, and a newly forming advisory group of patients, caregivers, front-line clinicians, health system business administrators and leaders, government and community organizations, and dementia researchers.  The research agenda will focus on questions that target the most important challenges to these stakeholders, and will contribute to filling evidence gaps to influence the future of dementia care.  The advisory group will not only help define and prioritize relevant research questions, but it will also help us to consider the outcomes that matter most. To this end, T-CAR just submitted a PCORI Pipeline to Proposal Tier I grant proposal earlier in the week.  In the coming year, T-CAR will also focus on writing and publishing several papers about electronic medical record data quality, issues concerning prioritizing dementia from a public health perspective, and the business case for developing a dementia program for health systems. We are very excited about this new direction for T-CAR.

“The best classroom in the world is at the feet of an elderly person.” ~Andy Rooney

As young girls from East St. Paul, my sisters and I had very little parental supervision. In fact, all of my childhood friends had parents who worked long hours and allowed us rascals to roam the neighborhood, free and wild. I honestly think the only reason any of us survived into adulthood was because of the elders who lived on our block. They taught us to ride bikes, to perform first aid, to do repairs. They showed us the value of recycling, gardening, crocheting, laughing, and respecting one another on all occasions. It is so important for us, as a society, to take care of our older people, and to do whatever we can to keep them happy and in their homes throughout their final years of life. As it turns out, I’d like to be one of those old people someday too – and I hope to be treated and cared for in the best way possible.

This article was featured in MPR over the weekend:
http://www.mprnews.org/story/2016/03/20/alzheimers-at-school

The author does a great job of highlighting the need for schools to integrate dementia and AD education into their curriculums as our society continues to rapidly age. With increasing frequency, children will be impacted as their loved elders lose their memories and personalities; it certainly seems prudent to open these discussions in our schools (thanks for sharing this story, Beth).

Dementia can rob a person of how they have envisioned their life growing old. So often, people eventually enter nursing home or a skilled nursing facility where they’re treated for behavioral problems with side-effect ridden medication. Important work is being done to develop nonpharmacologic interventions for persons with dementia. It is difficult (or sometimes even impossible) to design truly rigorous studies for this kind of intervention. But these developments are moving forward, and they are inspiring.

This last weekend I attended Meeting of the Minds, where I learned about Scripted-IMPROV^TM. The Scripted-IMPROV^TM intervention was designed to address The Four A’s of Alzheimer’s: Anxiety, Agitation, Aggression, and Apathy. Funded by the NIA and NIH, and conducted by the Hearthstone Institute, it was the largest Phase 2 Clinical Trial of a major non-drug intervention for Alzheimer’s and dementia. I won’t get into too much detail, but the study found statistically significant increases in engagement and quality of life measures, as well as a decrease in depression measures. Results also indicated a decrease in appearance of The Four A’s. To learn more, and watch videos, visit the website: http://scriptedimprov.com/videos/

This week at the Grossman Center, we have been talking about the ways in which we represent our center, our science, and our discoveries to the community. These discussions have led us to consider various scientific communication issues that can arise as research is transmitted to the public.  As our center grows, we hope to communicate our work—through our website, social media, and in our annual reports—in a clear, accurate, and inspired way.

As scientists, we have an obligation to share our discoveries, as they contribute to the growing body of knowledge that advances medicine and improves humankind. At the same time, we strive to gain the recognition that ultimately fuels our ability to obtain funding and attract collaborators. Therefore, uniquely communicating our research, findings, and vision to the public is incredibly important

Our own work aside, we have all heard sensationalized science stories in the media—the research findings and medical advances that get blown out of proportion. It is true that amazing scientific discoveries are made with increasing frequency, and some of these discoveries rule out long-held scientific beliefs. But most discoveries are incremental pieces of a much larger puzzle. While some discoveries hold true through years of retesting and refining, many do not, and the public can become frustrated with scientific reports because they are often confusing and fickle.  This is not good for the community, and it is not good for the scientific method.

Along these lines, Beth shared a presentation given by Joe Palca, a science journalist for NPR. He argued that science makes for good stories, but not necessarily good news. News is about today, stories are good anytime. Science simply does not “play well” with news cycle timelines. I would also contend that it does not always “play well” with funding or report cycles either. We must remain vigilant in our communication so as not to get swept up in the hype – and to remain true to the science and our own methods. Communication between scientists and the masses is challenging; the language barriers and level of expectation can vary greatly.

At the Scientist Meeting last Friday, Kathy Zahs presented about Nilotinib, a fairly new cancer drug that has been reported to also have astounding effects on people suffering from Parkinson’s disease. We have been discussing this drug as a possible candidate for our own clinical trial with Alzheimer’s patients. The question is a touchy one since most of the data that sparked the hype about Nilotinib is still not fully understood, and the sample sizes for these studies are quite small. However, as these studies have been widely reported in the media, some patients suffering from Parkinson’s have been asking their medical provider for the drug. Suffering patients and families are paying close attention, and they are grasping for hope. Kathy did a wonderful job discussing the research, findings, and questions surrounding Nilotinib, and we undoubtedly will have many more conversations before any decisions are made. The bottom line is that we cannot let hope and hype make those kinds of decisions for us. We, as scientists, have a significant role to play in managing community expectations, and ultimately gaining widespread trust in our work.

This week, we challenge you to find other examples of hope, hype, and sensational news stories about scientific and medical discoveries. What was the role of the scientists in those particular circumstances? Also, feel free to share any ideas about communicating our research to the public through our website, social media, or other outlets.