Related Experiment Video
Updated: Jul 31, 2025
Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
Oligomeric β-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway
Ya-Li Wang1, Jian-Gang Wang1, Shuling Guo2
1Department of Physiology and Pathophysiology, Henan International Joint Laboratory of Non-Invasive Neuromodulation, Xinxiang Medical University, Xinxiang, China.
Abstract:
Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aβ1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aβ1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aβ1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aβ1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aβ1-42-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 Aβ1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aβ1-42 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 Aβ1-42 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.
Insights
Alzheimer's disease (AD) impairs brain gamma oscillations via amyloid-beta. Targeting the mTOR/S6K1 pathway restores oscillations and may treat early cognitive decline in AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Neuronal synchronization at gamma frequency (30-100 Hz) is crucial for cognitive function.
- Gamma oscillations are impaired in early-stage Alzheimer's disease (AD).
- Oligomeric amyloid-beta (Aβ) is implicated in AD pathogenesis and neuronal dysfunction.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Aβ-induced gamma oscillation impairment in early AD.
- To identify potential therapeutic targets for restoring gamma oscillations in AD.
Main Methods:
- Electrophysiological recordings of gamma oscillations in brain slices and in vivo.
- Pharmacological manipulation of mTOR/S6K1 signaling pathway.
- Assessment of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs).
- Studies in Aβ-overexpressing APP/PS1 mouse models.
Main Results:
- Oligomeric Aβ₁-42 reduced gamma oscillation strength and regularity in a concentration-dependent manner.
- Inhibition of mTOR/S6K1 signaling, but not eIF4E, prevented Aβ₁-42-induced gamma oscillation suppression.
- Aβ₁-42 reduced excitatory and inhibitory synaptic transmission, which was rescued by mTOR/S6K1 inhibition.
- Inhibition of mTOR or S6K1 restored gamma oscillations in APP/PS1 mice.
Conclusions:
- Oligomeric Aβ₁-42 impairs gamma oscillations in early AD by activating the mTOR/S6K1 pathway.
- This impairment is mediated by reduced inhibitory interneuron activity.
- Targeting the mTOR/S6K1 pathway offers a potential therapeutic strategy for early AD cognitive decline.
