Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology

Lee SY, Park E, Lee HE, Kim S, Yeo Y, Park J, Choi YJ, Lee K, Yoon KJ, Park S, Kim E, Kim JI · 2026 · Nature · Atlas ID LEE2026

What this study shows

Ectopic ERBB4 in excitatory neurons is one of the earliest changes in AD mouse models and is both necessary and sufficient for synapse loss, reactive gliosis, amyloid deposition and cognitive deficits — and these effects require mTOR signalling downstream of ERBB4. Places mTOR as a required mediator in an early neuronal driver of AD pathology, upstream of the glial and amyloid phenotypes.

Abstract

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

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse AD models (5xFAD/APP), excitatory-neuron-specific Erbb4 deletion and overexpression; human AD single-nucleus transcriptomics); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mouse AD models (5xFAD/APP), excitatory-neuron-specific Erbb4 deletion and overexpression; human AD single-nucleus transcriptomics
Journal	Nature
Year	2026
Peer reviewed	Yes
Record last updated	2026-08-22
Source	DOI 10.1038/s41586-026-10964-z · PMID 42649291

Extracted findings

Intervention	Excitatory-neuron-specific Erbb4 deletion and Erbb4 overexpression; mTOR pathway inhibition
Target	ERBB4 -> mTOR signalling in excitatory neurons
Model	Mouse; human transcriptomic data
Effect	Erbb4 deletion rescued synapse loss, gliosis, amyloid deposition and cognitive deficits; Erbb4 overexpression recapitulated AD-like phenotypes — both requiring mTOR signalling downstream

Cite this paper

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Lee, S. Y., Park, E., Lee, H. E., Kim, S., Yeo, Y., Park, J., Choi, Y. J., Lee, K., Yoon, K. J., Park, S., Kim, E., Kim, J. I., & Chung, W. S. (2026). Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology. Nature. https://doi.org/10.1038/s41586-026-10964-z

@article{LEE2026,
  author       = {Lee, S. Y. and Park, E. and Lee, H. E. and Kim, S. and Yeo, Y. and Park, J. and Choi, Y. J. and Lee, K. and Yoon, K. J. and Park, S. and Kim, E. and Kim, J. I. and Chung, W. S.},
  title        = {{Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology}},
  journal      = {Nature},
  year         = {2026},
  doi          = {10.1038/s41586-026-10964-z},
  note         = {PMID: 42649291},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record LEE2026) [Data set]. https://mtor-atlas.org/study/LEE2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_LEE2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record LEE2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/LEE2026/},
  doi          = {10.5281/zenodo.22059963}
}