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

Neuronal synchronization at gamma frequency (30-100 Hz: gamma) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric A beta(1-42) caused a concentration-dependent reduction of gamma-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the A beta(1-42)-induced suppression of gamma-oscillations, whereas the mTOR activator leucine mimicked the A beta(1-42)-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the A beta(1-42)-induced suppression. The involvement of the mTOR/S6K1 signaling in the A beta(1-42)-induced suppression was confirmed in A beta-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded gamma-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated gamma-oscillation impairment in AD, we tested the effect of A beta(1-42) on IPSCs and EPSCs recorded in pyramidal neurons. A beta(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 A beta(1-42) impairs gamma-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.

Automated summary

Neuronal synchronization at gamma frequency is impaired in early-stage Alzheimer's disease. The study found that oligomeric A beta(1-42) reduces the strength and regularity of gamma oscillations while increasing its frequency. The mTOR/S6K1 signaling pathway plays a key role in the A beta(1-42)-induced suppression of gamma oscillations.