Korean researchers identify key switch driving Alzheimer's progression

Dementia devastates not only patients but their families — and Korean scientists may now be a step closer to stopping it.

A South Korean research team has identified a key molecular switch that triggers the vicious cycle of memory and cognitive decline in dementia. Blocking that single switch restored neural circuits in the brain and sharply reduced both inflammation and amyloid plaques.

The Ministry of Science and ICT announced Thursday that a team led by Jung Won-seok, deputy director of the Institute for Basic Science's Center for Vascular Research and associate professor of biological sciences at KAIST, has identified ERBB4 as the core regulatory factor driving the cascading pathological progression of Alzheimer's disease. The finding offers what researchers describe as a fundamental key to breaking the chain of neural circuit destruction — a process that has long resisted treatment because its underlying cause was unknown.

The results were published in the international journal Nature.

Alzheimer's disease is a degenerative brain disorder characterized by the abnormal accumulation of amyloid beta in the brain. About 10 million people worldwide are living with the condition, and cases are increasingly being reported among people in their 20s and 30s.

In patients' brains, amyloid buildup is accompanied by a complex mix of neural circuit hyperexcitability, synaptic loss and glial cell inflammation. Treatments targeting amyloid removal have been developed, but researchers have long noted their limited effectiveness in improving cognitive function.

The research team focused on an imbalance in neural circuits and synapses that appears in the early stages of the disease. Analysis of the hippocampus in Alzheimer's model mice showed that excitatory neurons — which stimulate brain circuits — were excessively activated, while the activity of inhibitory neurons that regulate them had fallen sharply.

Astrocytes and microglia were found to be aggressively eliminating excitatory synapses, further deepening the circuit imbalance.

Tracing the cause at the molecular level, the team found that ERBB4 receptors were markedly elevated in a specific population of excitatory neurons. The researchers named these cells "early responsive excitatory neurons," or ERENs.

When the team used gene-editing technology to selectively remove ERBB4 from excitatory neurons in Alzheimer's model mice, the excessive activity of those neurons subsided. The activity of some inhibitory neurons that had declined also recovered.

Abnormal synaptic elimination and inflammatory responses by glial cells were likewise reduced. Notably, the area and number of amyloid plaques — a hallmark of Alzheimer's disease — fell by more than 50 percent. Memory and spatial cognition also improved significantly.

Conversely, when ERBB4 was expressed in excitatory neurons of healthy mice, Alzheimer's-like changes appeared — including neural circuit hyperexcitability, synaptic imbalance and glial inflammation — even in the complete absence of amyloid plaques.

Analysis of brain tissue from 446 individuals further confirmed that ERBB4 expression was significantly elevated in the excitatory neurons of Alzheimer's patients. Higher ERBB4 levels correlated with greater amyloid plaque accumulation and more severe cognitive decline.

"This research offers new clues for understanding the amplification process of Alzheimer's disease from multiple angles," Jung said. "We expect that combining treatment to remove amyloid beta with treatment to eliminate ERBB4 could yield considerable results."