Autophagy-ERK1/2-Involved Disinhibition of Hippocampal Neurons Contributes to the Pre-Synaptic Toxicity Induced by Aβ 42 Exposure

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most frequent cause of progressive cognitive decline in the elderly population. To date, there is still no effective treatment for AD, requiring more underlying mechanisms. In the present study, we investigated the effects of Aβ₄₂ on the inhibitory synaptic transmission in the cultured hippocampal neurons, and explored the possible mechanism. The frequency, but not amplitude, of miniature inhibitory post-synaptic currents was significantly suppressed by Aβ₄₂, indicating that Aβ₄₂ played its role in inhibitory transmitter release at the pre-synaptic sites. Aβ₄₂ had no effect on miniature excitatory post-synaptic currents, suggesting GABAergic synapses are more susceptible to Aβ₄₂ exposure. However, the number of GABAergic neurons or synapses was not influenced, suggesting the corresponding stage may be a preclinical one. The effect of Aβ₄₂ can be mimicked by PD98059 (an inhibitor of ERK1/2) and blocked by curcumin (an activator of MEK), which reveals Aβ-involved influence is via the decreased phosphorylation of MAPK-ERK1/2. In addition, synaptophysin is confirmed to be a downstream protein of MAPK-ERK1/2 at the pre-synaptic site. At the same time, suppressed autophagy was observed after Aβ₄₂ exposure, and the activation of autophagy increased pERK1/2 level and salvaged the disinhibition of hippocampal neurons. These data suggest that diminished GABAergic tone likely starts from the preclinical stage of AD, so some GABAergic stress test may be effective for identifying cognitively normal elder adults. Strategies against the dysfunction of autophagy should be adopted in the early stage of AD because of its initial effects.