We all have a vivid image of a grandparent, a friend, a mother, a father, an aunt, or uncle who was diagnosed with Alzheimer’s disease.

Perhaps their memory isn’t what it was. Maybe they act differently. In all, and most devastating, the person you knew and loved just isn’t who they are anymore.

For the past hundred years, the scientific community has studied Alzheimer’s disease following one theory. This theory has been that Alzheimer’s is caused by the buildup of plaques (a protein called amyloid) and tangles (a protein called tau). However, because treatments targeting these plaques and tangles have consistently failed, my research has taken a fresh approach to studying Alzheimer’s. 

Instead of studying amyloid and tau, we study tiny cellular machines that signal the brain how to function correctly. These machines are called kinases. Proper brain function depends on kinases working together.

In Alzheimer’s disease, brain cells slowly die. It has become the focus of my research to find how brain cells die in Alzheimer’s.

To describe my research, I think it is best to play a game of Clue. In this story, we know the brain is our victim. If you have ever played Clue, then you know that you must identify the suspect, the weapon, and the room that causes the brain to die.

In my lab, we believe that kinases, or the way kinases work together, somehow go bad in brain diseases. Using a new technology called the Kinome Array, we identified one suspect kinase called AMPK. AMPK is very important because it controls how human cells use energy. When a cell doesn’t have a lot of energy, AMPK becomes activated. This activation gives the cell the energy it needs.

I studied the expression and activity of AMPK in Alzheimer’s human brain. I discovered that AMPK expression was lowered in the Alzheimer’s brain. Even more, AMPK was not as activated in the Alzheimer’s brain. This was our first clue that AMPK may be our suspected killer.

Every suspected killer has a weapon. To find the weapon, I had to find the other machines (proteins) that AMPK works with. I found the weapon by studying the proteins that are known to work with AMPK. I started looking more closely at a protein called YAP1. AMPK attaches a molecule called a phosphate to YAP1. It turns out that phosphate-bound-YAP1 signals cells to enter a pro-death state.

Because brain cells die in Alzheimer’s, this could be a very powerful interaction. Indeed, phosphate-bound-YAP1 was higher in the Alzheimer’s disease brain. With this information, I found my suspect’s weapon.

Now that I had evidence that it may be AMPK using YAP1 as a weapon, I needed to finish my game of Clue. The next step was finding what room (that is, what part of the brain cell) that AMPK interacts with YAP1. To find this room, I took samples of human postmortem brain and isolated all the different rooms that we can find in a cell. I was most interested in studying the nucleus of these brain cells because the nucleus is the cell’s Office and Library. It is where work is done, knowledge is stored, and orders are written for all cell workers.

After isolating the different cellular rooms, amazingly, there was a higher amount of AMPK in the nucleus of Alzheimer’s brain. When AMPK is higher in the nucleus, it tells brain cells to die. This discovery, with the YAP1 findings, suggested I may have won my game of Clue.

In the end, it was AMPK (my suspect) with YAP1 (it’s weapon) in the nucleus (the room).

The AMPK /YAP1 story in Alzheimer’s disease does not end here. The mystery of what truly causes Alzheimer’s disease needs to be solved. My work has generated so many exciting research questions: How can we target this interaction to slow the disease? Can we diagnose Alzheimer’s before it is irreversible? May we prevent the loss of identify of the people we love?

My answers to these questions are what drive the passion for my research. Since 2020, I have lost three grandparents to dementia. This work is completed to honor their memory. I am grateful for the University of Toledo College of Medicine and Life Sciences and the Cognitive Disorder Research Laboratory for providing me this opportunity of research and discovery.

Nicholas Henkel is an M.D./Ph.D. student in the Department of Neurosciences at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Henkel is conducting his research with Dr. Robert Smith. For more information, contact Nicholas.Henkel@utoledo.edu or go to utoledo.edu/med/grad/biomedical.

First Published July 3, 2023, 11:00 a.m.