2022 Alzheimer's Association Research Fellowship (AARF)

Acetylcholine Levels Impact on Hippocampal Activity and Memory

What is the relationship between brain cell communication, brain changes, and cognition in Alzheimer’s? 

Coralie-Anne Mosser, Ph.D.
Douglas Hospital Research Centre
Montreal, Canada

Background

Nerve cells in the brain communicate by releasing and sensing signaling molecules called neurotransmitters. Neurotransmitters bind to docking sites called “receptors” on the surface of nerve cells and activate pathways in these cells, which is inherent to how the brain functions. One neurotransmitter, called acetylcholine, is particularly important for attention and memory. Nerve cells that use acetylcholine to communicate with one another are known as cholinergic nerve cells and they are a vital part of the brain’s communication network. Studies show that the loss of cholinergic neurons negatively affects attention and the formation of new memories. People with Alzheimer’s tend to have a decreased number of cholinergic nerve cells which limits the amount of nerve cell connections in the brain and can make it harder for brain cell networks to communicate.
 
Drugs called acetylcholinesterase inhibitors, which broadly increase levels of acetylcholine, have only proven modestly successful in individuals with Alzheimer’s. Researchers are investigating other ways to keep acetylcholine in the brain to help support brain cell to cell communications. One of these ways is through modulating a protein called VAChT (vesicular acetylcholine transporter) that is responsible for storing the acetylcholine. Though preliminary studies suggest that changes in VAChT can impact Alzheimer’s progression and cognition, the biological mechanisms underlying the relationship between changes in communication, Alzheimer’s-related brain changes, and cognition is unknown.

Research Plan

Dr. Coralie-Anne Mosser and colleagues will study how VAChT levels impact Alzheimer’s-related brain changes and cognition in two types of genetically engineered Alzheimer’s-like mice. One type of mouse is genetically engineered to lack VAChT. The other type is engineered to have two Alzheimer’s-related genetic changes in addition to lacking VAChT. The researchers will simultaneously record acetylcholine activity and nerve cell activity in a brain region called the hippocampus (which is important in learning and memory and is impacted by Alzheimer’s) in these mice as they perform a memory task in the laboratory.

Impact

The results may contribute to our understanding of the role of cholinergic nerve cells in the progression of Alzheimer’s and inform the development of novel therapeutics.

This Project has been made possible by the Canada Brain Research Fund (CBRF), an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada Foundation, and of the Alzheimer’s Association. To date, Health Canada has invested over $130 million through the CBRF which has been matched by Brain Canada Foundation and its donors and partners.