After failing to find ways of removing the brain plaques responsible for the disease, researchers now say they have another way of tackling Alzheimer’s worst symptoms that leaves the plaques in place.
Reporting in the journal Neuron, Dr. Stephen Strittmatter, professor of neurology at Yale University School of Medicine, describes a missing link in the Alzheimer’s disease process that could lead the way to new drug-based treatments. Alzheimer’s is characterized by the presence of sticky deposits of a protein called amyloid, which the human body makes naturally, but tends to accumulate in the brains of Alzheimer’s patients. As the plaques grow, they starve nerve cells, cutting off their ability to communicate with other cells via synapses, leading to their death and to the symptoms of memory loss, dementia and impaired thinking that are signs of advanced disease.
For decades, scientists have focused on finding ways to remove the plaque – either with a drug or a vaccine, but all have either failed or shown limited success. Researchers have tried to contain the accumulation of amyloid both by interfering with its production as well as accelerating processes that clear the protein, but to no avail.
Strittmatter and his colleagues, however, recently turned their attention to another part of the Alzheimer’s process — figuring out how the amyloid leads to nerve cell death. They knew that while the body makes amyloid, only one form of the protein, an oligomer, tended to glom together and cause the problematic plaques. They also knew that the plaques somehow became toxic to nerve cells. A year ago, the team identified how the amyloid plaques and nerve cells interact – via a prion protein on the surface of the nerve cells that has a special affinity for the amyloid oligomer. They also documented what happened inside nerve cells exposed to the toxic amyloid. But they still didn’t know how the binding to amyloid outside of the cell triggered the often fatal changes inside the neuron.
Until now. The team says that they have found the receptor, one that binds the brain chemical glutamate, that ties the entire disease-process together. Even more exciting, says Strittmatter, there are drugs that can block the activity of this receptor and therefore stop the toxic processes responsible for Alzheimer’s.
“This could play out so for patients in the early stages of the disease, who have lost some memory, we could restore some memory but not all memory, and hopefully halt the progression of the disease,” he says. “That’s exciting.”
He and his colleagues have already tested this potential therapy in mice that model Alzheimer’s. When they gave the animals a drug that blocked activity of the specific glutamate receptor, “we rescued the animals; their memory and synapses came back to normal,” he says.
The strategy does not do anything to existing deposits of amyloid in the brain; they remain intact, but the idea is to block the plaques’ toxic effects on nerve cells, protecting their ability to communicate with each other via synapses and maintain thinking functions. Whether it’s necessary to remove the plaques as well isn’t clear yet, but Strittmatter says there is no reason both strategies wouldn’t be considered in coming years.
The next step will be to calibrate how much drug is needed to block the glutamate receptor in question – normal human brains need glutamate for almost every excitatory response – so completely shutting down its activity isn’t feasible. But having another way to nip at the amyloid plaques in Alzheimer’s is a welcome advance – and could turn the tide of battle against the disease for millions of patients in coming decades.