In mice, rogue ERBB4 signal drives Alzheimer’s pathology

Inside a mouse brain, a receptor had appeared in the wrong kind of neuron. Chung Won-Suk and colleagues at the Institute for Basic Science found abnormal ERBB4 expression in excitatory neurons early in Alzheimer’s disease models, where the signal was followed by circuit hyperactivity, synapse loss, glial activation, amyloid accumulation and impaired memory.

ERBB4 helps cells receive and transmit signals. In a healthy brain, it is expressed mainly by inhibitory neurons, which help keep neural circuits from becoming overexcited. In the disease models, a subset of excitatory neurons—the cells that drive circuit activity—switched it on instead. The researchers named these cells Early Responsive Excitatory Neurons, or ERENs.

The team first observed astrocytes and microglia, two supporting brain-cell types, selectively engulfing more excitatory synapses and fewer inhibitory ones. Increasing neuronal activity increased this synapse engulfment; suppressing activity reduced it. Targeted removal of Erbb4 from hippocampal excitatory neurons then dampened hyperactivity, corrected abnormal synaptic changes, reduced reactive glia and lowered amyloid plaque burden. It also improved performance in several memory and spatial-cognition tests. The ERBB4–mTOR signaling pathway emerged as a major route connecting the neuronal signal to these effects.

The result is not yet a human therapy. When researchers activated ERBB4 in a small subset of excitatory neurons in otherwise healthy mice, the animals developed several Alzheimer’s-like features without amyloid plaques, suggesting that the signal can sit upstream of more than one pathology. In human postmortem samples and transcriptomic data from 446 individuals, higher ERBB4 expression in excitatory neurons was associated with greater amyloid burden and poorer cognitive performance; statistical modeling also linked it to amyloid pathology, later tau pathology and cognitive decline. Those associations do not prove that ERBB4 directly causes Alzheimer’s disease in people.

So what changes, concretely? The study points researchers toward a possible early target that could influence several disease features at once rather than treating plaques in isolation. But the evidence remains at the mouse-model and human-observation stages: the study identifies a promising biological control point, while an ERBB4-targeted treatment has not been established for patients.