Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
Margaret O'Connor,
Yang-Ping Shentu,
Guan Wang,
Wen-Ting Hu,
Zhen-Dong Xu,
Xiao-Chuan Wang,
Rong Liu,
Heng-Ye Man
Affiliations
Margaret O'Connor
Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
Yang-Ping Shentu
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Guan Wang
Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
Wen-Ting Hu
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Zhen-Dong Xu
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Xiao-Chuan Wang
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Rong Liu
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Corresponding author
Heng-Ye Man
Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA; Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 72 East Concord St., L-603, Boston, MA 02118, USA; Center for Systems Neuroscience, Boston University, 610 Commonwealth Avenue, Boston, MA, USA; Corresponding author
Summary: 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 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.
