A beta-Induced Synaptic Alterations Require the E3 Ubiquitin Ligase Nedd4-1

作者：Rodrigues Elizabeth M; Scudder Samantha L; Goo Marisa S; Patrick Gentry N^*

来源：Journal of Neuroscience, 2016, 36(5): 1590-1595.

DOI：10.1523/JNEUROSCI.2964-15.2016

• abeta
• AMPA receptor
• endocytosis
• Nedd4-1
• ubiquitin

Alzheimer's disease (AD) is a neurodegenerative disease in which patients experience progressive cognitive decline. A wealth of evidence suggests that this cognitive impairment results from synaptic dysfunction in affected brain regions caused by cleavage of amyloid precursor protein into the pathogenic peptide amyloid-beta (A beta). Specifically, it has been shown that A beta decreases surface AMPARs, dendritic spine density, and synaptic strength, and also alters synaptic plasticity. The precise molecular mechanisms by which this occurs remain unclear. Here we demonstrate a role for ubiquitination in A beta-induced synaptic dysfunction in cultured rat neurons. We find that A beta promotes the ubiquitination of AMPARs, as well as the redistribution and recruitment of Nedd4-1, a HECT E3 ubiquitin ligase we previously demonstrated to target AMPARs for ubiquitination and degradation. Strikingly, we show that Nedd4-1 is required for A beta-induced reductions in surface AMPARs, synaptic strength, and dendritic spine density. Our findings, therefore, indicate an important role for Nedd4-1 and ubiquitin in the synaptic alterations induced by A beta.

• 出版日期2016-2-3