A new study could open the door to help Alzheimer’s disease patients improve their learning and memory function through new treatments. Researchers from Fujita Health University made the key discovery as they identified the intracellular signal cascade through which the neuromodulator acetylcholine regulates aversive learning.
Study authors report that the Alzheimer’s drug donepezil activates this signal cascade to regulate aversive learning, indicating the potential of the signaling cascade for drug targeting.
“Acetylcholine (ACh) is a neuromodulator with a central role in aversive learning—rapid conditioning to unpleasant smell, taste, or touch. These learning functions play out in cells called D2 receptor-expressing medium spiny neurons (D2R-MSNs) that are located in the striatum/nucleus accumbens (NAc) of the brain,” the researchers explain.
Fujita Health University researchers were able to make clear the molecular mechanisms of ACh for learning and memory.
“This is the first time this has been achieved in the 45 years since the cholinergic hypothesis of AD (Alzheimer’s disease) was established. Our study also led us to understand the intracellular mechanism of donepezil and its effect on learning and memory. This exciting discovery opens doors to new therapeutic strategies for AD,” says Dr. Yukie Yamahashi, assistant professor and study lead author, in a statement.
A process known as phosphorylation facilitates molecular signaling cascades. This involves the addition of phosphate groups to certain substrate molecules by kinases within cells. Researchers employed a technique called kinase-oriented phosphorproteomic analysis to study phosphorylation.
“This study constitutes the first evidence for the intracellular mechanisms of donepezil that regulate learning and memory,” says Dr. Yamahashi.
Since the study’s finding imply the signal cascade is involved in recognition memory and associative learning, the cascade offers a platform for screening Alzheimer’s drugs undergoing development.
“We are only seeing the tip of the iceberg and believe future research could yield novel mechanisms of signal transduction in other brain areas,” says Dr. Yamahashi.
The study was published in the journal Molecular Psychiatry.