ERBB4: the early driver protein reversing Alzheimer's pathology in neurons

ERBB4 overexpression in excitatory neurons emerges as a central driving mechanism in Alzheimer's onset and progression, according to single-nucleus RNA sequencing analysis revealing the early appearance of early-responsive excitatory neurons (EREN) characterized by this aberrant protein signature. Selective deletion of Erbb4 in excitatory neurons of Alzheimer's models completely abrogated abnormal neuronal activity, synapse loss, reactive gliosis, amyloid plaque deposition, and cognitive deficits; conversely, its overexpression in wild-type neurons recapitulated these core phenotypes without amyloid pathology, suggesting ERBB4 acts downstream of mTOR, the pivotal aging regulator. Transcriptomic analysis of human Alzheimer's data supports a model where neuronal ERBB4 links the pathogenic cascade from amyloid pathology through tau propagation to cognitive decline. For the longevity-focused reader, this represents an intervention point upstream of classical amyloid accumulation, potentially opening new therapeutic vectors across neurodegeneration.