AETA peptide contributes to Alzheimer’s disease signature of synapse dysfunction
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.
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BibTeX
@article{dunot2026aeta,
title = {{AETA peptide contributes to Alzheimer’s disease signature of synapse dysfunction}},
author = {Jade Dunot and Carine Gandin and Marin Truchi and Giulia Pirro and Sébastien Moreno and Agathe Launay and Benjamin Azoulay and Hugo Landra and Sandy Ma Yishan and Luc Buée and Kevin Lebrigand and Paula A Pousinha and David Blum and Bernard Mari and Ingrid Bethus and Michael Willem and Hélène Marie},
journal = {Acta Neuropathologica},
year = {2026},
month = jun,
doi = {10.1007/s00401-026-03033-2},
url = {https://hal.science/hal-05790172v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AETA peptide contributes to Alzheimer’s disease signature of synapse dysfunction
AU - Jade Dunot
AU - Carine Gandin
AU - Marin Truchi
AU - Giulia Pirro
AU - Sébastien Moreno
AU - Agathe Launay
AU - Benjamin Azoulay
AU - Hugo Landra
AU - Sandy Ma Yishan
AU - Luc Buée
AU - Kevin Lebrigand
AU - Paula A Pousinha
AU - David Blum
AU - Bernard Mari
AU - Ingrid Bethus
AU - Michael Willem
AU - Hélène Marie
PY - 2026
DA - 2026/06/03
JO - Acta Neuropathologica
DO - 10.1007/s00401-026-03033-2
UR - https://hal.science/hal-05790172v1
AB - 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.
SN - 0001-6322
SN - 1432-0533
ER -