A domestic research team has identified a key factor that sequentially worsens neural circuit abnormalities and inflammatory responses in Alzheimer's disease.
The Ministry of Science and ICT said that the research team led by Deputy Director Jeong Won-seok of the Institute for Basic Science (IBS) Vascular Research Center has found that the ERBB4 receptor promotes an imbalance in neural circuits during the progression of Alzheimer's disease. The findings were published in Nature on the 27th.
Alzheimer's disease is characterized by the accumulation of amyloid beta in the brain, but in the actual course of the disease, excessive excitation of neurons, synapse loss, and inflammatory responses also appear together. That is why there has been criticism that amyloid-clearing treatments alone have limited effectiveness.
The researchers analyzed the hippocampus of an Alzheimer's disease model mouse and confirmed that the activity of excitatory neurons increases excessively, while the activity of neurons that suppress them decreases. As astrocytes and microglia excessively removed excitatory synapses, circuit imbalance also worsened.
In this process, the team discovered that the protein ERBB4 increases markedly in specific excitatory neurons. When they then used gene-editing technology to remove ERBB4 from excitatory neurons, neuronal hyperexcitability, synapse loss, and inflammatory responses were alleviated. The area and number of amyloid plaques fell by more than 50%, and memory and spatial cognition also improved.
Conversely, when ERBB4 was expressed in the excitatory neurons of normal mice, Alzheimer's-like changes—such as neural circuit hyperexcitability, synaptic imbalance, and inflammatory responses—appeared even without amyloid plaques.
The researchers also confirmed that the increase in ERBB4 excessively activates mTOR signaling, which regulates cell growth and metabolism, thereby spreading pathology. An analysis of brain tissue from 446 people likewise showed increased ERBB4 expression in the excitatory neurons of patients with Alzheimer's disease, and the greater the expression, the more severe the amyloid accumulation and cognitive decline tended to be.
Deputy Director Jeong Won-seok said, "This study offers clues to understand how various pathological phenomena in Alzheimer's disease are amplified," adding, "It could lead to therapeutic strategies that target key regulatory factors to alleviate complex pathologies together."
References
Nature (2026), DOI: https://doi.org/10.1038/s41586-026-10964-z