Excitatory Neuronal ErbB4 Drives Early Pathophysiology of Alzheimer's Disease

Neuroinflammation and synapse loss synergistically contribute to cognitive decline in Alzheimer’s disease (AD). Although microglial hyper-phagocytic activity has been shown to mediate synapse loss, the exact mechanisms underlying these pathologies remain obscure. Here, we first demonstrate that astrocytes and microglia increase the phagocytic elimination of excitatory synapses, but significantly decrease their elimination of inhibitory synapses during AD progression, suggesting neuroinflammation may be dispensable for early AD synapse loss. Instead, through single-nucleus RNA sequencing (snRNAseq), we identified Disease-Initiating Excitatory Neurons (DIENs), characterized by ectopic Erbb4 expression, as the earliest alteration in an AD mouse model. Notably, specific deletion of Erbb4 in 5XFAD excitatory neurons abrogated abnormal neuro-network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition, and cognitive deficits. Conversely, overexpression of Erbb4 in wild-type excitatory neurons recapitulated key AD phenotypes, including cognitive impairment. Subsequent snRNAseqs following Erbb4 deletion and overexpression confirm that excitatory neuronal Erbb4 is both sufficient and necessary to induce DIEN and reactive gliosis. Together, these findings reveal that the early pathophysiology of AD arises largely due to aberrant Erbb4 expression in excitatory neurons, and that targeting excitatory neuronal Erbb4 may thus represent a novel therapeutic strategy for mitigating AD progression.