Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease

作者：Zhang, Yanmin; Guo, Ouyang; Huo, Yuda; Wang, Guan; Man, Heng-Ye^*

来源：Journal of Alzheimer's Disease, 2018, 62(4): 1789-1801.

DOI：10.3233/JAD-170879

• Alzheimer's disease
• amyloid-beta
• AMPA receptor
• degradation
• Nedd4
• ubiquitination
• USP46

As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer's disease (AD), presumably via amyloid-beta (A beta). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of A beta triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both A beta-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of A beta. Furthermore, AD brain lysates and A beta-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the A beta-dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD.

• 出版日期2018
• 单位山东大学