A sticky protein implicated in Alzheimer’s disease disrupts the brain’s circuitry by inducing seizures that give barely an outward sign that they’re happening, a study of mice shows.
Excessive buildup of a protein called amyloid-beta in the brain is a hallmark of Alzheimer’s disease, and scientists have long suspected that this protein plays a deleterious role in the disease.
In the new study, amyloid-beta triggered excessive firing of neurons, leading to subtle seizures in parts of the mouse brain that are central to memory and learning, says study coauthor Lennart Mucke, a neurologist at the Gladstone Institute of Neurological Disease at the University of California, San Francisco. The episodes fall short of causing the jerking motions or convulsions seen in some epileptic seizures, which could explain why their occurrence in mice with an Alzheimer’s-like condition had gone largely unnoticed. The findings appear in the Sept. 6 Neuron.
Mucke and his colleagues tested mice that were genetically engineered to overproduce amyloid-beta. By age 4 to 7 months, the mice began to show cognitive problems, such as losing their way in a familiar maze. However, the animals’ neurons hadn’t died, says Mucke. Rather, the mice began to lose function at their synapses, the junctions at which neurons pass messages to one another.
Mucke likens neurons to trees in a forest, with the tip of each branch representing a potential synapse for relaying messages to another neuron. “A tree can lose branches and leaves but still be alive,” he says. In the mice, the neurons survived, but the messaging network was damaged after their brains became inundated with the amyloid-beta proteins.
Previous studies have shown memory and learning deficits in such engineered mice. In the new study, the researchers implanted electrodes in the brains of some of the mice and tracked their brain function using electroencephalogram (EEG) readings as the mice moved freely about their cages. When a mouse was having a miniseizure, as evident from its EEG readouts, it sometimes froze in its tracks.
Biochemical and anatomical analyses of the brains of these mice revealed high concentrations of neuropeptide Y, a chemical typically released to calm overexcited neurons. In this case, the protective reaction may be overcompensating for the problem of excessive signaling. “In mice with the most severe memory deficits, neuropeptide Y tended to be at maximal levels,” Mucke says.
The net effect is dull signaling that depresses the mouse brain’s agility, possibly paralleling symptoms in Alzheimer’s patients, the scientists conclude.
“This is an important study for sure, suggesting that amyloid-beta isn’t just causing neuron death but is also pruning back synapses,” says neurobiologist Rudolph Tanzi of Harvard Medical School and Massachusetts General Hospital in Boston. “This adds to a growing body of literature on amyloid-beta deposition. I think this is just the tip of the iceberg. It’s a great start toward understanding more about how amyloid-beta deposits disrupt neural circuitry.”
Mucke and his team are designing a trial that would use EEG readings to test for small seizures in people with early-stage Alzheimer’s disease.