A South Korean research team has identified ‘ERBB4’, a key regulatory factor that sequentially aggravates the diverse pathologies of Alzheimer’s disease. By controlling a single target, the team has opened the door to a new therapeutic strategy capable of easing multiple pathologies at once.
 [코리안투데이] IBS Center for Vascular Research Senior Researcher Lee Se-young (left) and Associate Director Won-Suk Chung © 장형임 기자 |
The Ministry of Science and ICT (Deputy Prime Minister and Minister of Science and ICT Bae Kyung-hoon) announced that a research team led by Won-Suk Chung, Associate Director of the Center for Vascular Research at the Institute for Basic Science (IBS, President Jang Seok-bok) and Associate Professor in the Department of Biological Sciences at KAIST, has identified a key regulatory factor that disrupts the balance of neural circuits and synapses in Alzheimer’s disease and sequentially worsens disease progression. The study was carried out with support from the Ministry’s IBS basic science research program and was published in Nature, one of the world’s most prestigious international journals, at 0:00 (KST) on August 27.
Alzheimer’s disease is a representative degenerative brain disorder marked by declining memory and cognitive function, and its main feature is the abnormal accumulation of amyloid-beta in the brain. However, as the disease advances, complex changes appear together — including excessive excitation of neural circuits, synapse loss, and inflammatory responses of glial cells — which is why therapies that remove amyloid have shown only limited effect despite being developed. The possibility that multiple pathologies influence one another and worsen the disease had been repeatedly raised, but the fundamental factor triggering this vicious cycle had not been clearly identified.
The researchers focused on the imbalance between neural circuits and synapses that appears from the early stages of the disease. Analyzing the hippocampus of mouse models of Alzheimer’s disease, they found that excitatory neurons, which stimulate brain circuits, were excessively activated, while the activity of inhibitory neurons, which suppress them, dropped sharply. In addition, astrocytes and microglia excessively removed excitatory synapses while removing fewer inhibitory synapses, further fueling the imbalance. By artificially raising neuronal activity, the researchers observed that glial cells removed more synapses, and by lowering it, they removed fewer — demonstrating that the cause of the synapse-loss imbalance lies in the abnormal activity state of neurons.
Tracing the cause at the molecular level, the researchers found that the ERBB4 receptor, normally present in inhibitory neurons of the healthy brain, was markedly increased in a specific population of excitatory neurons. They named these cells ‘early responsive excitatory neurons (EREN)’ and pinpointed ERBB4 as the key factor causing circuit abnormalities.
When the researchers used gene-editing technology to selectively remove ERBB4 only in the excitatory neurons of Alzheimer’s model mice, the excessive activity of excitatory neurons decreased and the diminished activity of some inhibitory neurons recovered. The abnormal synapse removal and inflammatory response of glial cells were also eased, and the area and number of amyloid plaques dropped by more than 50 percent. As a result, memory and spatial cognition improved significantly. Conversely, when ERBB4 was expressed in the excitatory neurons of normal mice, the same pathological changes seen in Alzheimer’s disease — circuit hyperexcitation, synaptic imbalance, and glial inflammatory responses — appeared even in the complete absence of amyloid plaques.
The researchers also proved the mechanism by which increased ERBB4 excessively activates the ‘mTOR’ signaling system, which regulates cell growth and metabolism, causing the pathology to spread to surrounding areas. In an analysis of brain tissue from 446 people, ERBB4 expression in the excitatory neurons of Alzheimer’s patients was significantly elevated, and the higher the expression level, the greater the accumulation of amyloid plaques and the more severe the cognitive decline. This confirmed that changes in ERBB4 are not merely a phenomenon accompanying Alzheimer’s disease but a key regulatory factor that drives the sequential progression of multiple pathologies.
Unlike previous research that treated amyloid accumulation, microglial immune responses, synapse loss, and neural circuit abnormalities as separate phenomena, this achievement is significant in that it presents an overarching regulatory axis encompassing them all. In particular, by verifying both the necessity and the sufficiency of ERBB4 and clarifying its operating pathway through mTOR signaling, the team laid the groundwork for exploring therapeutic strategies that ease multiple pathologies together, moving beyond approaches that target only a single lesion. This is seen as a step forward that opens new treatment possibilities for patients and families facing degenerative brain diseases that have been difficult to cure.
The team plans to further study how ERBB4 changes during aging, as well as what role ERBB4 plays in other degenerative brain diseases such as Parkinson’s disease, Huntington’s disease, and tau-related disorders, in order to explore its potential as a therapeutic target common to multiple diseases.
Won-Suk Chung, IBS Associate Director, said, ‘These findings offer a new clue for understanding the amplification process of Alzheimer’s disease from multiple angles,’ adding, ‘We expect this to contribute to pioneering a new therapeutic strategy that targets the core link in the disease’s vicious cycle and simultaneously eases complex and diverse pathologies.’ Kim Sung-soo, Director-General of Research and Development at the Ministry of Science and ICT, said, ‘The key to overcoming intractable diseases comes from fundamental inquiry into the principles of life,’ and pledged, ‘We will continue our steady support so that basic science remains a firm pillar protecting the healthy lives of the people.’
지역 홍보대사 신청 기자양성과정 신청 코리안투데이 지부장 신청 코리안투데이 인천강화코리안브랜드대상 신청 최고경영인대상 신청 소비자만족도대상 신청
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