AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction.
Overview
- Université Côte d’Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire,Valbonne, France
- Univ. Lille, INSERM, CHU Lille, UMR-S1172 LilNCog-Lille Neuroscience and Cognition,Lille, France
- Munich Cluster for Systems Neurology (SyNergy),Munich, Germany
- Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), Ludwig-Maximilians-Universität München,Munich, Germany
Abstract
Alzheimer’s disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice displayed an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.
Supplementary Information: The online version contains supplementary material available at 10.1007/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE333329, at NCBI GEO; found in “Availability of data and materials”
Availability of data and materials
All RNA sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under serie accession number GSE333329 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Publisher: n/a → Springer Science+Business Media
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 5 keywords, 15 MeSH terms, 6 funders, 52 references.
Cite
This paper
Dunot, J., Gandin, C., Truchi, M., Pirro, G., Moreno, S., Launay, A., Azoulay, B., Landra, H., Yishan, S. M., Buée, L., Lebrigand, K., Pousinha, P. A., Blum, D., Mari, B., Bethus, I., Willem, M., & Marie, H. (2026). AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction. Acta neuropathologica, 151(1), 65. https://
BibTeX
@article{dunot2026aeta,
author = {Dunot, Jade and Gandin, Carine and Truchi, Marin and Pirro, Giulia and Moreno, Sébastien and Launay, Agathe and Azoulay, Benjamin and Landra, Hugo and Yishan, Sandy Ma and Buée, Luc and Lebrigand, Kevin and Pousinha, Paula A. and Blum, David and Mari, Bernard and Bethus, Ingrid and Willem, Michael and Marie, Hélène},
title = {{AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction}},
journal = {Acta neuropathologica},
year = {2026},
month = jun,
volume = {151},
number = {1},
pages = {65},
publisher = {Springer Science+Business Media},
issn = {0001-6322},
doi = {10.1007/
url = {https://
pmid = {42237024},
pmcid = {PMC13233929}
}
RIS
TY - JOUR
AU - Dunot, Jade
AU - Gandin, Carine
AU - Truchi, Marin
AU - Pirro, Giulia
AU - Moreno, Sébastien
AU - Launay, Agathe
AU - Azoulay, Benjamin
AU - Landra, Hugo
AU - Yishan, Sandy Ma
AU - Buée, Luc
AU - Lebrigand, Kevin
AU - Pousinha, Paula A.
AU - Blum, David
AU - Mari, Bernard
AU - Bethus, Ingrid
AU - Willem, Michael
AU - Marie, Hélène
TI - AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction
T2 - Acta neuropathologica
J2 - Acta Neuropathol
PY - 2026
DA - 2026/
VL - 151
IS - 1
SP - 65
SN - 0001-6322
PB - Springer Science+Business Media
DO - 10.1007/
UR - https://
LA - en
ER -
CSL-JSON
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