Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
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AMPA 受体的乙酰化调节受体运输并挽救阿尔茨海默氏病的记忆缺陷
DOI：
10.1016/j.isci.2020.101465
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发表时间：
2020
期刊：
影响因子：
5.8
通讯作者：
Heng-Ye Man
中科院分区：
文献类型：
--
作者：
Margaret O'Connor;Yang-Ping Shentu;Guan Wang;Wen-Ting Hu;Zhen-Dong Xu;Xiao-Chuan Wang;Rong Liu;Heng-Ye Man
在阿尔茨海默病（AD）中，AMPA受体（AMPAR）的量和突触定位的减少导致突触活性减弱和突触可塑性功能障碍，从而导致认知功能障碍。我们以前已经发现，AMPAR受到赖氨酸乙酰化，导致更高的AMPAR稳定性和蛋白质积累。在这里，我们报告说，AMPAR乙酰化显着减少AD和神经元与抗体孵育。我们鉴定了p300作为负责AMPAR乙酰化的乙酰转移酶，并发现增强GluA 1乙酰化改善了Ab诱导的总AMPAR和细胞表面AMPAR的减少。重要的是，乙酰化模拟物GluA 1（GluA 1 -4KQ）在APP/PS1小鼠中的表达挽救了突触可塑性和记忆的损伤。这些发现表明Ab诱导的AMPAR乙酰化和稳定性的降低有助于AD中的突触病和记忆缺陷，表明AMPAR乙酰化可能是AD治疗的有效分子靶点。
In 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 Ab incubation. We identi-fied p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Ab-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 Ab-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.