Aβ-Induced Synaptic Alterations Require the E3 Ubiquitin Ligase Nedd4-1

J Neurosci. 2016 Feb 3;36(5):1590-5. doi: 10.1523/JNEUROSCI.2964-15.2016.


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-β (Aβ). Specifically, it has been shown that Aβ 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 Aβ-induced synaptic dysfunction in cultured rat neurons. We find that Aβ 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 Aβ-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 Aβ.

Significance statement: Synaptic changes in Alzheimer's disease (AD) include surface AMPAR loss, which can weaken synapses. In a cell culture model of AD, we found that AMPAR loss correlates with increased AMPAR ubiquitination. In addition, the ubiquitin ligase Nedd4-1, known to ubiquitinate AMPARs, is recruited to synapses in response to Aβ. Strikingly, reducing Nedd4-1 levels in this model prevented surface AMPAR loss and synaptic weakening. These findings suggest that, in AD, Nedd4-1 may ubiquitinate AMPARs to promote their internalization and weaken synaptic strength, similar to what occurs in Nedd4-1's established role in homeostatic synaptic scaling. This is the first demonstration of Aβ-mediated control of a ubiquitin ligase to regulate surface AMPAR expression.

Keywords: AMPA receptor; Nedd4-1; abeta; endocytosis; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Amyloid beta-Peptides / physiology
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Humans
  • Male
  • Nedd4 Ubiquitin Protein Ligases
  • Rats
  • Receptors, AMPA / metabolism
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synapses / pathology
  • Ubiquitin-Protein Ligases / metabolism*


  • Amyloid beta-Peptides
  • Endosomal Sorting Complexes Required for Transport
  • Receptors, AMPA
  • NEDD4L protein, rat
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Nedd4 protein, rat
  • Ubiquitin-Protein Ligases