Calcineurin inhibition prevents synaptic plasticity deficit induced by brain-derived tau oligomers

Abstract

Compelling evidence suggests that cognitive decline in Alzheimer's disease is associated with the accumulation and aggregation of tau protein, with the most toxic aggregates being in the form of oligomers. This underscores the necessity for direct isolation and analysis of brain-derived tau oligomers from patients with Alzheimer's disease, potentially offering novel perspectives into tau toxicity. Alzheimer's brain-derived tau oligomers are potent inhibitors of synaptic plasticity; however, the involved mechanism is still not fully understood. We previously reported a significantly reduced incidence of Alzheimer's disease in ageing humans chronically treated with a Food and Drug Administration-approved calcineurin inhibitor, FK506 (tacrolimus), used as an immunosuppressant after solid organ transplant. Using a combination of electrophysiological and RNA-sequencing techniques, we provide here evidence that FK506 has the potential to block the acute toxic effect of brain-derived tau oligomers on synaptic plasticity, as well as to restore the levels of some key synaptic mRNAs. These results further support FK506 as a promising novel therapeutic strategy for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; FK506; LTP; tacrolimus; tau.

Graphical Abstract

Figure 1

FK506 prevents hippocampal synaptic plasticity impairment induced by BDTO. Hippocampal slices from C57BL/6J mice (age: 8–12 weeks) underwent a 1-h pre-treatment with either standard holding solution or holding solution + BDTO (100 µM) prior to electrophysiological recording. Slices exposed to BDTO were then recorded using regular aCSF or aCSF + FK506 (10 µM). Field recordings were conducted with the stimulation electrode in the Schaffer collateral and the recording electrode in the Stratum Radiata of CA1 pyramidal neurons. Stimulation intensity was set to evoke 30% of maximal response. (A) Representative current traces of LTP protocol, average of 30 sweeps for baseline (10 minutes) and 180 sweeps post-HFS (60 min). (B) Slope percentage of fEPSP. (C) Slope average over the final 10 min showing FK506’s prevention of LTP impairment by BDTO (half-brain slices each group: CTRL n = 11; BDTO n = 7; BDTO + FK506 n = 8). (D) Representative current traces of PP stimulation protocol, average on 10 sweeps over 3 min, interstimulus interval (ISI) was 50 ms. (E) PP ratio indicating a trend towards impairment in the BDTO group compared with control and a significant reduction versus BDTO + FK506. Minimum of three different mice each group, each point represents data from a single half-brain slice (CTRL n = 11; BDTO n = 7; BDTO + FK506 n = 8, see the Statistical analysis section for criteria of exclusion). Statistical analysis involved one-way ANOVA followed by Tukey’s post hoc test.

Figure 2

Heat map illustrating PEA of DEGs in CTRL, BDTO and BDTO + FK506 groups. DEGs were identified using an FDR P-value threshold in pairwise comparisons (e.g. CTRL > BDTO refers to genes upregulated in CTRL compared with BDTO; BDTO > CTRL refers to genes upregulated in BDTO compared with CTRL). Enrichment analysis involved accumulative hypergeometric P-values and enrichment factors (gene ontology terms). A hierarchical clustering approach was employed to categorize experimental groups. The heat map’s value scale ranges from 0 (indicating non-significance) to 20 (representing statistical significance in gene expression variations between groups). The analysis highlights specific pathways and gene expressions modulated differently across treatment conditions (CTRL n = 11; BDTO n = 7; BDTO + FK506 n = 7, see the Statistical analysis section for criteria of exclusion). U1 snRNP, U1 small nuclear ribonucleoprotein; SWI/SNF, switch/sucrose non-fermentable; AP-1, activator protein 1.

Figure 3

Synaptic gene expression and correlation with electrophysiological parameters. (A) Venn diagram illustrating the overlap and uniqueness of DEGs across different treatment groups. (B, C) Pearson’s correlation analysis between synaptic DEGs and electrophysiological measurements from Fig. 1 (LTP and PP ratios). Genes upregulated in CTRL and BDTO + FK506 groups compared with BDTO (C) show a positive correlation with electrophysiological measurements, whereas genes upregulated in BDTO compared with CTRL and BDTO + FK506 (D) demonstrate a negative correlation. The data suggest a distinct gene expression profile in the BDTO group that inversely correlates with synaptic plasticity measures. The list of the genes in Supplementary Table 4.