Oligomeric β-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aβ(1-42) caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aβ(1-42)-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aβ(1-42)-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aβ(1-42)-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aβ(1-42)-induced suppression was confirmed in Aβ-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aβ(1-42) on IPSCs and EPSCs recorded in pyramidal neurons. Aβ(1-42) reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aβ(1-42) impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.