摘要：SummaryIn Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.Graphical AbstractDisplay OmittedHighlights•AMPAR acetylation is reduced in AD brain and neurons with Aβ incubation•p300 is the acetyltransferase for AMPAR acetylation•Up-regulation of AMPAR acetylation in neurons blocks Aβ-induced receptor internalization•Expression of GluA1 acetylation mimetic rescues cognitive deficits in APP/PS1 miceBehavioral Neuroscience; Molecular Neuroscience; Cellular Neuroscience
