NatureAug 26, 2026

Abnormal activity of a brain cell receptor linked to Alzheimer's disease

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Updated Aug 27, 2026

Abstract

Astrocytes and microglia in Alzheimer's disease mice increase the elimination of excitatory synapses while decreasing the removal of inhibitory synapses.

Neuroinflammation and synapse loss are linked to cognitive decline in Alzheimer's disease.
The increase in phagocytic activity by astrocytes and microglia may not require neuroinflammation for early synapse loss.
Early-responsive excitatory neurons, marked by ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4) expression, emerge as a significant early alteration in Alzheimer's disease models.
Deleting Erbb4 in excitatory neurons prevents abnormal network activity, synapse loss, reactive gliosis, amyloid plaque deposition, and cognitive deficits.
Overexpressing Erbb4 in normal excitatory neurons mimics key Alzheimer's disease features without the presence of amyloid plaques.
ERBB4's effects on synapse loss and other Alzheimer's characteristics depend on mTOR signaling pathways.

Simplified

Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss^1-4, 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.

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Abnormal activity of a brain cell receptor linked to Alzheimer's disease

Abstract

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