The longstanding cholinergic hypothesis proposes that the cholinergic system — a network of neurons which passes information through a chemical messenger known as acetylcholine — becomes dysfunctional in Alzheimer’s disease.
Some drug developers have put stock in the cholinergic hypothesis, developing a type of medication known as cholinesterase inhibitors. While Alzheimer’s still has no cure, according to clinicians cholinesterase inhibitors — such as donepezil (Aricept), which is approved by the Food and Drug Administration to treat Alzheimer’s — may temporarily ease its symptoms and can improve the quality of people’s lives. But some scientists may have overlooked the effectiveness of the drugs because cholinesterase inhibitors don’t defeat Alzheimer’s.
Banner Alzheimer’s Institute Director Pierre Tariot, who studied the effects of cholinergic drugs for people with Alzheimer’s, told Being Patient: “A lot of experts in the field say that drugs like cholinesterase inhibitors ‘aren’t important.’ That puzzles me.”
“I would request that somebody who thinks that to spend one day in our clinic and listen to the stories that our families tell of the impact of treatment — the mother and wife who regained the ability to dress independently, or who went from gargled speech to intelligible speech, or who regained the ability to empty the dishwasher — I could go on and on,” he said.
What Is Acetylcholine and How Is It Related to Alzheimer’s?
Scientists designed cholinesterase inhibitors to target the dysfunctional cholinergic system and improve communication between neurons. According to Varghese John, a professor and medicinal chemist who leads the Drug Discovery Laboratory at the Department of Neurology at University California Los Angeles, presynaptic neurons release acetylcholine as a piece of information used to form memory. The acetylcholine then binds onto various receptors of other neurons called postsynaptic neurons.
Presynaptic neurons become damaged in Alzheimer’s, releasing less acetylcholine as they begin to die. Cholinesterase inhibitors help sustain levels of acetylcholine where neurons connect by blocking an enzyme, known as acetylcholinesterase, from breaking down the neurotransmitter. That way, the neurons have a higher chance of passing information through the neurotransmitter.
“The disease progression is ongoing, so the presynaptic neuron that is diseased is going to die off,” John said.
While neurons normally produce only small amounts of beta-amyloid peptide, they sometimes ramp up their production of the peptides, overwhelming other brain cells, like microglial cells that would normally help clear up the beta-amyloid. They then accumulate into plaques, a hallmark of Alzheimer’s.
Meanwhile, tau protein, which is part of the structure of neurons, begins to degrade, twisting and forming into what’s known as tau oligomers. Here, the diseased presynaptic neurons can release these tau oligomers. They bind onto some of the receptors of healthy postsynaptic neurons. These neurons can then consume the tau oligomers, spreading the disease.
“It’s a way by which the forest fire can spread,” John said.
The accumulation of beta-amyloid, tau and the death of neurons can occur over the course of more than 20 years until people present clinical symptoms of Alzheimer’s.
John and colleagues are now developing drugs to block these healthy neurons from absorbing tau oligomers, which may help prevent the progression of Alzheimer’s.