<< Back

2023 Alzheimer's Association Research Fellowship (AARF)

Restoring Excitation-Inhibition Balance in Alzheimer’s Disease Mouse Models

How does nerve cell activity become imbalanced in the Alzheimer’s brain and how can such imbalance be treated?
 

Moustafa Algamal, Ph.D.
Massachusetts General Hospital
Boston, MA - United States



Background

In the brains of individuals with Alzheimer’s, two proteins, beta-amyloid and tau, tend to become misshapen and accumate into  beta-amyloid plaques and tau tangles which are the hallmark brain changes in Alzheimer’s. Research has found that plaques and tangles may alter the function of certain nerve cells, including those that stimulate brain activity (known as “excitatory” neurons) and those that inhibit brain activity (or “inhibitory” neurons). Such alterations can lead to an “imbalance” of activity in the brain, including the activity of synapses (the specialized structures that nerve cells use to send signals to one another and communicate). Studies also show that brains with inhibited activity may develop memory loss and other forms of cognitive decline in Alzheimer’s.

In initial research, Dr. Moustafa Algamal and colleagues studied a group of specialized nerve cells called “somatostatin-expressing” (SOM) interneurons which inhibit communication between other nerve cells. They found that these cells become overly active around beta-amyloid plaques. This finding, along with other study results, suggest that SOM interneurons reduce the activity of excitatory neurons, lower overall brain cell communication and promote cognitive decline.  

Research Plan

Dr. Algamal and team will now conduct a larger study of interneurons and brain activity in Alzheimer’s using  two groups of genetically engineered Alzheimer’s-like mice. First, the researchers will chemically inhibit SOM interneurons in one group of mice that develop beta-amyloid plaques to assess whether this treatment restores excitatory nerve cell function and prevents memory loss, beta-amyloid clumping and other disease-related changes. Next, the team will study a group of mice engineered to develop Alzheimer’s-related tau. Previous research has found that tau may reduce nerve cell activity and promote cognitive decline. Using a brain scan method that involves a fluorescent protein (a molecule that can bind to and “highlight” individual brain cells), Dr. Algamal and colleagues will measure activity levels in the mice’s inhibitory and excitatory neurons. They will then inhibit SOM interneurons in the animals and, once again, assess how this treatment may stimulate excitatory nerve cell activity and restore cognitive function.

Impact

The results of this project could refine our understanding of how nerve cell activity balance in the brain becomes altered in Alzheimer’s. They could also identify SOM interneurons as a target for novel Alzheimer’s treatments.

Back to Top