This report highlights recently published research investigating the role of abnormal ERBB4 expression in excitatory neurons during the development and progression of Alzheimer’s disease.
ERBB4 is a receptor tyrosine kinase that is normally associated primarily with inhibitory neurons in the central nervous system. In this study, researchers identified an unusual population of excitatory neurons expressing ERBB4 early in Alzheimer’s disease mouse models. These cells were described as early-responsive excitatory neurons, or ERENs.
The researchers found that aberrant ERBB4 expression in excitatory neurons was associated with neuronal hyperactivity, altered excitatory and inhibitory synapse balance, increased synapse elimination by astrocytes and microglia, reactive gliosis, amyloid beta plaque accumulation, and cognitive impairment.
Importantly, selectively reducing Erbb4 expression in excitatory neurons improved several Alzheimer’s disease-related abnormalities in mouse models, while increasing Erbb4 expression in healthy mice reproduced many AD-like neuronal, synaptic, and glial changes even in the absence of amyloid plaques.
The study further identified mammalian target of rapamycin, or mTOR, signaling as a key downstream pathway mediating ERBB4-related effects. Human brain tissue and transcriptomic analyses also showed increased excitatory neuronal ERBB4 in Alzheimer’s disease and linked ERBB4-associated neuronal populations with greater pathological burden and poorer cognitive performance.
- Researchers identified an early population of excitatory neurons with abnormal ERBB4 expression in Alzheimer’s disease mouse models.
- These ERBB4-expressing excitatory neurons were associated with increased neuronal excitability and disruption of normal excitatory–inhibitory network balance.
- During disease progression, astrocytes and microglia increased elimination of excitatory synapses while reducing elimination of inhibitory synapses.
- Selective deletion of Erbb4 in excitatory neurons reduced abnormal neuronal activity, synapse loss, reactive gliosis, amyloid plaque burden, and cognitive deficits in Alzheimer’s disease mouse models.
- Overexpression of Erbb4 in healthy excitatory neurons reproduced major AD-like neuronal, synaptic, and glial abnormalities even without detectable amyloid plaques.
- mTOR signaling was identified as an important downstream mediator of ERBB4-induced pathological changes.
- Human Alzheimer’s disease brain tissue showed increased ERBB4 expression in excitatory neurons compared with non-demented controls.
- In human transcriptomic data, ERBB4-high excitatory neuronal populations were associated with greater amyloid plaque severity and poorer cognitive performance.
- The findings suggest that aberrant excitatory neuronal ERBB4 may act as both a consequence and amplifier of Alzheimer’s disease pathology and may represent a potential therapeutic target.
Access the full peer-reviewed Nature publication describing how aberrant ERBB4 expression in excitatory neurons influences neuronal activity, synapse elimination, glial responses, amyloid pathology, mTOR signaling, and cognitive decline in experimental models and human Alzheimer’s disease datasets.
View Full Publication