ERBB4 Perturbation Supports a Developmental Cytoskeletal Reactivation Hypothesis in Alzheimer’s Disease
- 1Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, USA
Abstract
Background
Aberrant reactivation of developmental cytoskeletal programs may contribute to Alzheimer's disease (AD). We tested whether a prespecified Arp2/3-RAC1-MYH10-KIF5C module is regulated by Erb-B2 receptor tyrosine kinase 4 (ERBB4) in an AD-model neuronal state, providing a perturbational test of the hypothesis that aberrant re-engagement of developmental cytoskeletal machinery contributes to AD.Methods
We performed a secondary analysis of publicly available single-nucleus RNA-sequencing data from ERBB4 perturbation experiments using pseudobulk analysis with the primary conservative excitatory-neuron classifier. A prespecified 10-gene module comprising Actr2, Actr3, Arpc1a, Arpc2, Arpc3, Arpc4, Arpc5, Rac1, Myh10, and Kif5c was tested using CAMERA and expression-matched permutation analyses.Results
ERBB4 disruption in 5 × FAD excitatory neurons downregulated all 10 module genes (CAMERA P = 0.0207). Arpc4, Arpc1a, and Kif5c remained significant after false-discovery-rate correction. Expression-matched permutation testing independently supported pathway downregulation (mean log-fold-change P = 0.0102; 10/10 genes down P = 0.0041; CAMERA permutation P = 0.0150). ERBB4 overexpression in wild-type neurons did not significantly alter the complete module, although Arpc5 was significantly induced, suggesting selective component responsiveness.Conclusions
Independent perturbational data support ERBB4-dependent regulation of a prespecified Arp2/3-centered cytoskeletal program in AD excitatory neurons, with effects dependent on the disease context.
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BibTeX
@article{lehrer2026erbb4,
title = {{ERBB4 Perturbation Supports a Developmental Cytoskeletal Reactivation Hypothesis in Alzheimer’s Disease}},
author = {Steven Lehrer},
journal = {Cureus},
year = {2026},
month = sep,
doi = {10.7759/cureus.117166},
url = {https://europepmc.org/article/PMC/PMC13718877},
note = {CC BY},
}
RIS
TY - JOUR
TI - ERBB4 Perturbation Supports a Developmental Cytoskeletal Reactivation Hypothesis in Alzheimer’s Disease
AU - Steven Lehrer
PY - 2026
DA - 2026/09/29
JO - Cureus
DO - 10.7759/cureus.117166
UR - https://europepmc.org/article/PMC/PMC13718877
AB - Background Aberrant reactivation of developmental cytoskeletal programs may contribute to Alzheimer's disease (AD). We tested whether a prespecified Arp2/3-RAC1-MYH10-KIF5C module is regulated by Erb-B2 receptor tyrosine kinase 4 (ERBB4) in an AD-model neuronal state, providing a perturbational test of the hypothesis that aberrant re-engagement of developmental cytoskeletal machinery contributes to AD.Methods We performed a secondary analysis of publicly available single-nucleus RNA-sequencing data from ERBB4 perturbation experiments using pseudobulk analysis with the primary conservative excitatory-neuron classifier. A prespecified 10-gene module comprising Actr2, Actr3, Arpc1a, Arpc2, Arpc3, Arpc4, Arpc5, Rac1, Myh10, and Kif5c was tested using CAMERA and expression-matched permutation analyses.Results ERBB4 disruption in 5 × FAD excitatory neurons downregulated all 10 module genes (CAMERA P = 0.0207). Arpc4, Arpc1a, and Kif5c remained significant after false-discovery-rate correction. Expression-matched permutation testing independently supported pathway downregulation (mean log-fold-change P = 0.0102; 10/10 genes down P = 0.0041; CAMERA permutation P = 0.0150). ERBB4 overexpression in wild-type neurons did not significantly alter the complete module, although Arpc5 was significantly induced, suggesting selective component responsiveness.Conclusions Independent perturbational data support ERBB4-dependent regulation of a prespecified Arp2/3-centered cytoskeletal program in AD excitatory neurons, with effects dependent on the disease context.
SN - 2168-8184
ER -