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, …, Chung WS · 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 necessary for synapse loss, reactive gliosis, amyloid plaque deposition and cognitive deficits in AD mice, and its overexpression in wild-type excitatory neurons is sufficient to reproduce synapse loss, gliosis and cognitive deficits (but not amyloid plaques); these effects require mTOR signalling downstream of ERBB4.

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	2026-10-01
Source	DOI 10.1038/s41586-026-10964-z · PMID 42649291

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

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 plaque deposition and cognitive deficits; Erbb4 overexpression recapitulated these phenotypes without amyloid plaques - both requiring mTOR signalling downstream

In the Atlas

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}
}

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