A INCREASE IN APP-DERIVED PEPTIDE AETA DISTURBS BRAIN NETWORK DYNAMICS

The amyloid-β precursor protein (APP) is a transmembrane protein expressed in the brain and implicated in Alzheimer’s disease. We previously identified a novel cleavage site of APP, the η-secretase site, generating extracellular soluble peptides termed AETA (Aη-α or Aη-β, depending on subsequent α- or β-secretase processing). Our work showed that AETA modulates synaptic plasticity and reduces calcium activity in the hippocampus (HPC) in vivo by altering NMDA receptor–dependent transmission, inhibiting ionotropic activity while enhancing ion flux–independent signalling. These findings suggest that AETA may act as an endogenous modulator of hippocampal network dynamics. To investigate this possibility, we used the AETA-m mouse line, in which human AETA is produced and secreted in the brain. We performed in vivo local field potential recordings in the hippocampus (HPC) and medial prefrontal cortex (mPFC) of animals across behavioural states, with a focus on rapid eye movement (REM) sleep. We found that AETA reshapes network oscillations during REM sleep and awake state. HPC theta power was reduced in both the pyramidal and molecular layers. In parallel, AETA enhanced theta–gamma coupling within the hippocampus and between the HPC and mPFC. This increase in cross-frequency coupling was layer-specific and predominantly observed in the molecular layer. Together, these results indicate that AETA regulates state-dependent information routing within hippocampal circuits, potentially by modulating entorhinal inputs targeting the molecular layer and coordinating hippocampo–prefrontal communication during REM sleep. Our data identify AETA as a neuromodulatory signal shaping laminar-specific network dynamics relevant for sleep-dependent memory consolidation.