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Aberrant excitatory neuronal ERBB4 promotes Alzheimer’s disease pathology
Nature
(2026) Cite this article
Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer’s disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss1,2,3,4, the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for early AD synapse loss. Instead, single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in AD mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques. Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.
Synapse loss is evident across multiple brain regions from early stages of AD5,6. A prevailing model proposes that amyloid-β (Aβ) oligomers induce reactive microglial states and activate complement-dependent phagocytic programs, leading to excessive synapse elimination1,2,3,4. Previously, we revealed that astrocytes have a major role in the continuous elimination of both excitatory and inhibitory synapses in the normal adult hippocampus7. This astrocytic elimination of adult hippocampal synapses is highly dependent on hippocampal activity and has a critical role in maintaining circuit homeostasis and memory function7. As most research on the mechanisms of synapse loss in AD has focused on microglia and excitatory synapses, we initially set out to determine the contribution of astrocytes to the elimination of both excitatory and inhibitory synapses during AD progression.
Here we found that altered glial synapse elimination arises as a result of gene expression and functional changes in AD excitatory neurons. Using single-nucleus RNA-sequencing (snRNA-seq), gene set enrichment analysis (GSEA), weighted gene correlation network analysis (WGCNA) and candidate gene approach, we identified a single responsible pathway, an ectopically expressed ERBB4 tyrosine kinase receptor in excitatory neurons, as a key disease-promoting factor orchestrating broad aspects of AD pathophysiology. CRISPR-based Erbb4 knockout in excitatory neurons of the 5×FAD mouse model substantially normalized excitatory neuronal hyperactivity, inhibitory neuronal hypoactivity, abnormal synapse elimination, reactive gliosis and even Aβ accumulation, leading to significant recovery of cognitive functions. Conversely, restricted Erbb4 overexpression in wild-type (WT) excitatory neurons reproduced major AD-like phenotypes in the absence of Aβ plaques through downstream mTOR signalling. Human AD tissue and transcriptomic analyses further linked excitatory neuronal ERBB4 to amyloid and tau pathology and cognitive decline. These findings support a model in which early excitatory neuronal dysfunction, mediated by aberrant Erbb4 expression, precipitates maladaptive gl