Abstract

Abstract Compelling evidence suggests that cognitive decline in Alzheimer’s disease is associated with accumulation and aggregation of tau protein, with the most toxic aggregates being in 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 significantly reduced incidence of Alzheimer’s disease in aging humans chronically treated with a Food and Drug Administration-approved calcineurin inhibitor, FK506 (Tacrolimus), used as 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.