AETA peptide drives Alzheimer’s disease signature of synapse dysfunction
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INTRODUCTION
Alzheimer’s disease (AD), the leading cause of dementia, is marked by early synaptic dysfunction preceding cognitive decline. While amyloid-β and Tau remain central to AD research, other pathogenic factors are emerging. We investigated AETA, a novel amyloid precursor protein (APP)-derived peptide, as a mediator of synaptic pathology.
METHODS
AETA levels were measured in human AD brains, and the AETA-m mouse model expressing secreted human AETA was assessed at molecular, functional, and behavioral levels for AD-like phenotypes.
RESULTS
AETA was significantly elevated in AD brains, especially in females. AETA-m mice displayed hippocampal synaptic gene expression patterns resembling vulnerable human AD regions, disrupted NMDA receptor signaling, dendritic spine loss, and mild hippocampal memory impairments, particularly in females, reflecting prodromal AD pathology.
DISCUSSION
These findings identify AETA as an additional driver of synaptic dysfunction and suggest its potential as a therapeutic target for early intervention in AD.
