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

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 A oligomers (AOs), 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 AOs transiently decreased intracellular ATP levels and AMPK activity, as evaluated by its phosphorylation at threonine residue 172 (AMPK-Thr(P)(172)). The AO-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 AO-induced inhibition of AMPK. Our results establish a novel toxic impact of AOs on neuronal metabolism and suggest that AO-induced, NMDA receptor-mediated AMPK inhibition may play a key role in early brain metabolic defects in AD.