Could one protein hold the key to Alzheimer’s? Korean researchers find new target.

A single protein may be fueling Alzheimer's progression. Korean researchers have identified a key driver of brain damage and a potential target for new treatments, according to the Ministry of Science and ICT on Thursday.

A team led by Chung Won-suk, associate director of the Center for Vascular Research at the Institute for Basic Science (IBS), identified Erbb4 as a key protein behind the breakdown of neural networks in the early stages of Alzheimer’s disease.

Alzheimer’s is a degenerative brain disease marked by memory loss and cognitive decline. One of its hallmarks is the buildup of amyloid beta, a toxic protein that forms sticky clumps in the brain. Scientists have long linked this buildup to an overactive immune response that destroys synapses, the connections that allow neurons to communicate.

Drugs that clear amyloid from the brain are already available, but their benefits have been limited. By the time Alzheimer’s progresses, several damaging processes can feed off one another. Removing amyloid alone is often not enough to break that cycle.

The IBS team, however, found a possible culprit behind that cycle.

The team focused on the fact that glial cells, which normally nourish neurons and clear damaged cells from the brain, were stripping away far more synapses from excitatory neurons than from inhibitory neurons in the early stages of Alzheimer’s.

The researchers traced the problem to Erbb4, a protein normally found in inhibitory neurons. In Alzheimer’s, however, unusually high levels of Erbb4 appeared in excitatory neurons, which play a key role in receiving signals and forming memories.

The abnormal buildup made these neurons overactive, which led glial cells to remove more of their connections. As more connections were lost, the brain’s neural network fell out of balance and amyloid buildup worsened.

The researchers used gene-editing technology to remove Erbb4 from the excitatory neurons of mice with Alzheimer’s.

The effects went beyond a single symptom. Hyperactive neurons stabilized, synapse damage eased and brain inflammation subsided. Toxic amyloid deposits also shrank by more than 50 percent in both amount and area. The mice performed significantly better in tests of memory and spatial awareness.

Interestingly, the opposite happened when researchers boosted Erbb4 in healthy mice. The animals began to show Alzheimer’s-like symptoms.

Evidence from human patients pointed in the same direction. An analysis of brain data from 446 people with Alzheimer’s found that higher Erbb4 levels were associated with more advanced disease and greater cognitive decline.

The results suggest that Erbb4 is more than a side effect of Alzheimer’s. The protein may act as a key switch that accelerates several of the disease processes at once.

That could make Erbb4 an important target for future drugs. Most Alzheimer’s treatments have focused on individual problems such as amyloid buildup or inflammation. Targeting Erbb4 could offer a way to tackle several of them together.

The study was published in the science journal Nature on Wednesday.

“Targeting a key link in the disease’s vicious cycle could contribute to the development of a new treatment strategy that addresses its many complex pathologies at the same time,” Chung said.

Turning the discovery into a drug, however, will not be simple. Erbb4 is also needed for normal brain function, so blocking the protein throughout the body could cause problems.

“Suppressing Erbb4 throughout the body could be dangerous, and technology that can selectively target specific types of brain cells will also be needed,” said Prof. Kim Dae-soo, in the Department of Brain & Cognitive Sciences at KAIST. “If we can precisely suppress Erbb4 only in the excitatory neurons responsible for memory, we may be able to stop dementia at an early stage.”

BY HONG SANG-JI [[email protected]]