标题: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
作者机构:[Zhang, Yanmin; Guo, Ouyang; Huo, Yuda; Wang, Guan; Man, Heng-Ye] Boston Univ, Dept Biol, 5 Cummington St, Boston, MA 02215 USA.; [Zhang, Yanmin] Sh 更多
通讯作者:Man, HY
通讯作者地址:[Man, HY]Dept Biol, 5 Cummington Mall, Boston, MA 02215 USA.
来源:JOURNAL OF ALZHEIMERS DISEASE
出版年:2018
卷:62
期:4
页码:1789-1801
DOI:10.3233/JAD-170879
关键词:Alzheimer's disease; amyloid-beta; AMPA receptor; degradation; Nedd4;; ubiquitination; USP46
摘要: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.
收录类别:SCIE
资源类型:期刊论文
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