According to researchers at the Institute for Basic Science (IBS), a misplaced molecular switch called ERBB4 acts as an early driver of multiple Alzheimer’s disease pathologies in mouse models, triggering neuronal hyperactivity, synapse loss, reactive gliosis, amyloid accumulation, and cognitive impairment when it turns on in excitatory neurons instead of inhibitory neurons.
How Misplaced ERBB4 Switches Drive Alzheimer’s Pathology
Alzheimer’s disease features multiple simultaneous breakdowns, including disappearing synapses, unstable neural circuits, reactive glial cells, and accumulating amyloid plaques. Scientists have long struggled to explain how these diverse abnormalities emerge together. To investigate, a research team led by Associate Director CHUNG Won-Suk at the Center for Vascular Research within the IBS examined glial cell activity in mouse models. The team found that astrocytes and microglia increasingly engulfed excitatory synapses while sparing inhibitory connections. By directly manipulating neuronal activity, the researchers discovered that glial cells were not acting alone, but were responding to abnormal signals coming from neurons.
Did you know? Single-nucleus RNA sequencing allows scientists to profile gene activity in individual cell nuclei.
The Discovery of Early Responsive Excitatory Neurons (ERENs)
Using single-nucleus RNA sequencing, the IBS team identified a distinct population of excitatory neurons emerging early in the disease process. These cells mistakenly turned on ERBB4, a receptor normally expressed mainly by inhibitory neurons to prevent neural circuits from becoming overexcited. The researchers named these cells “Early Responsive Excitatory Neurons,” or ERENs. When the team used targeted gene editing to selectively remove Erbb4 from hippocampal excitatory neurons in Alzheimer’s model mice, the intervention dampened neuronal hyperactivity, rebalanced inhibitory circuits, corrected synaptic changes, reduced reactive gliosis, lowered amyloid plaque burden, and improved spatial memory test performance.
Translating Murine Findings to Human Brain Tissue
To determine whether these findings might be relevant to people, the research team analyzed postmortem brain samples and transcriptomic data from 446 individuals. According to the study, published in Nature by Lee, S. Y., et al. (2026), human Alzheimer’s brains showed elevated ERBB4 expression in excitatory neurons. Higher levels of these cells correlated with greater amyloid plaque burden and poorer cognitive performance. Further statistical modeling linked ERBB4 to amyloid pathology, subsequent tau pathology, and cognitive decline. Further experiments identified mTOR signaling as a major pathway connecting ERBB4 activity with synaptic, glial, and cognitive abnormalities.
Frequently Asked Questions
What is ERBB4?
ERBB4 is a receptor normally found mainly on inhibitory neurons that helps cells receive and transmit signals. In Alzheimer’s disease models, it improperly appears in excitatory neurons.
Are ERBB4-targeted treatments ready for patients?
No. While the findings highlight ERBB4 as a potential early driver of pathological cascades, treatments targeting ERBB4 are not yet ready for clinical use.
How does ERBB4 affect memory and cognition?
Abnormal ERBB4 expression in excitatory neurons triggers neuronal hyperactivity, abnormal synapse elimination by glial cells, amyloid accumulation, and impaired memory.
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