Calcineurin inhibition prevents hippocampal synaptic plasticity impairment induced by brain‐derived tau oligomers via modulation of the transcriptome

Abstract

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) strongly correlates with tau protein accumulation, with the most toxic species being in form of oligomers [1,2]. Due to the polymorphism of tau oligomers, isolating and testing brain‐derived tau oligomers (BDTO) directly from AD patients could provide new insights into tau toxicity. BDTO are potent inhibitors of long‐term potentiation (LTP) in hippocampal brain slices [3], however the involved mechanism is still not fully understood. We previously reported significantly reduced incidence of AD in aging humans chronically treated with a FDA‐approved calcineurin inhibitor, FK506, used as immunosuppressant after solid organ transplant [4]. Here we show that impairment of the synaptic functionality driven by BDTO is restored by calcineurin inhibition using FK506 via selective transcriptomic changes.MethodCombination of electrophysiological and RNA‐seq techniques were used. Ex‐vivo slices from 8‐12 weeks old C67BL/6J mice were treated with aCSF (Ctrl), BDTO (100nM) or BDTO+FK506. Field excitatory post‐synaptic potentials (fEPSPs) recordings were performed by stimulating the Schaffer collateral pathway, and recording electrode was located at the junction of the alveus and cornu ammonius 1 (CA1). After electrophysiological recordings, the hippocampus was isolated from the brain slice, snap frozen and processed for RNA‐seq.ResultFK506 treatment significantly ameliorated the BDTO‐induced attenuation of fEPSP. One‐way ANOVA followed by Tukey’s test, showed that BDTO caused reduction of fEPSP compared to Ctrl (p = 0.068). fEPSP was re‐established at physiological levels in the group BDTO+FK506 (vs Ctrl p = 0.603; vs BDTO p = 0.0163). A similar trend was observed when we analyzed the paired‐pulse ratio. Analysis of the transcriptome showed that FK506 modulates key synaptic transcripts impaired after BDTO treatment.ConclusionOur study provides evidence that FK506 has the potential to block the BDTO toxic effect on synaptic plasticity. These results suggest that FK506 may represent a promising therapeutic strategy for the treatment of AD. Further research is needed to elucidate the precise molecular mechanisms underlying FK506‐mediated neuroprotection and to explore its potential in in vivo models of AD.