Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons

Gisele S. Seixas da Silva, Helen M. Melo, Mychael V. Lourenco, Natalia M. Lyra e Silva, Marcelo B. De Carvalho, Soniza V. Alves-Leon, Jorge M. De Souza, William L. Klein, Wagner S. Da-Silva, Sergio T. Ferreira, Fernanda G. De Felice*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

AMP-activated kinase (AMPK) is a key player in energy sensing and metabolic reprogramming under cellular energy restriction. Several studies have linked impaired AMPK function to peripheral metabolic diseases such as diabetes. However, the impact of neurological disorders, such as Alzheimer disease (AD), on AMPK function and downstream effects of altered AMPK activity on neuronal metabolism have been investigated only recently. Here, we report the impact of Aβ oligomers (AβOs), synaptotoxins that accumulate in AD brains, on neuronal AMPK activity. Short-term exposure of cultured rat hippocampal neurons or ex vivo human cortical slices to AβOs transiently decreased intracellular ATP levels and AMPK activity, as evaluated by its phosphorylation at threonine residue 172 (AMPK-Thr(P)172). The AβO-dependent reduction in AMPK Thr( P) 172 levels was mediated by glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype and resulted in removal of glucose transporters (GLUTs) from the surfaces of dendritic processes in hippocampal neurons. Importantly, insulin prevented the AβO-induced inhibition of AMPK. Our results establish a novel toxic impact of AβOs on neuronal metabolism and suggest that AβO-induced, NMDA receptor-mediated AMPK inhibition may play a key role in early brain metabolic defects in AD.

Original languageEnglish (US)
Pages (from-to)7395-7406
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Issue number18
DOIs
StatePublished - May 5 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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