A Protein Switched On in the Wrong Neurons May Drive Multiple Alzheimer's Pathologies

New research from South Korea's Institute for Basic Science (IBS) suggests that a broad range of Alzheimer's disease pathologies may be driven by a single molecular switch, a receptor called ERBB4, turning on in the wrong type of neuron. A team led by Associate Director Chung Won-Suk at the IBS Center for Vascular Research found that aberrant ERBB4 expression in excitatory neurons can trigger a chain reaction: neuronal hyperactivity, abnormal synapse loss, reactive glial cells, increased amyloid buildup and cognitive impairment. The findings are published in the journal Nature.

In the healthy brain, ERBB4 is expressed mainly by inhibitory neurons, which help prevent circuits from becoming overexcited. Using two mouse models of Alzheimer's disease, the researchers found that astrocytes and microglia, the brain's support cells, increasingly engulfed excitatory synapses while removing fewer inhibitory ones, a selective remodeling rather than a general increase in activity. When the team raised or suppressed neuronal activity directly, glial synapse engulfment rose or fell accordingly, suggesting the glial cells were responding to abnormal signals from neurons.

Single-nucleus RNA sequencing revealed a distinct population of excitatory neurons emerging early in disease that had switched on ERBB4, which the team named "Early Responsive Excitatory Neurons." Using targeted gene editing to remove Erbb4 from hippocampal excitatory neurons in Alzheimer's model mice dampened neuronal hyperactivity, corrected abnormal synaptic changes, reduced reactive changes in astrocytes and microglia, lowered amyloid plaque burden and improved memory and spatial cognition, even when the gene was removed after substantial disease progression. In the reverse experiment, switching ERBB4 on in a small subset of excitatory neurons in otherwise healthy mice produced circuit hyperactivity, synaptic imbalance, reactive gliosis and cognitive impairment, even without amyloid plaques.

Further experiments identified mTOR signaling as a major pathway through which ERBB4 produces its effects, placing the ERBB4-mTOR axis as a potentially important control point linking neuronal, synaptic, glial and cognitive abnormalities.

The team also examined postmortem brain samples and transcriptomic data from 446 individuals, finding elevated ERBB4 expression in excitatory neurons in Alzheimer's disease; higher levels were associated with greater amyloid plaque burden and poorer cognitive performance, and statistical modeling linked ERBB4 to amyloid pathology, subsequent tau pathology and cognitive decline. The researchers say this does not prove ERBB4 directly causes Alzheimer's in people, but supports the possibility that the abnormal neuronal state identified in mice also occurs in the human brain.