Figure 6
From: Novel use of FDA-approved drugs identified by cluster analysis of behavioral profiles
Model of interacting signaling pathways. Calcineurin-NFAT signaling can be suppressed using the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506). In contrast, proINDY activates calcineurin-NFAT signaling, by inhibiting an inhibitor (DYRK1A). Calcineurin inhibitors and proINDY have opposite effects on various behaviors, suggesting that calcineurin-NFAT signaling plays a key role in the regulation of neural function26. Various lines of evidence suggest that calcineurin signaling is activated in Alzheimer’s disease11,12. Oxidative stress, mitochondrial dysfunction and amyloid β (Aβ) oligomers contribute to increased intracellular free calcium (Ca2+), which activates calcineurin. Activated calcineurin dephosphorylates various signaling proteins, such as NFAT, BAD and GSK-3, which in turn induce various hallmarks of Alzheimer’s disease. Cabozantinib (XL184), one of the CsA-type drugs identified in the current study, is known to suppress proteins upstream of calcineurin signaling. VEGFR vascular endothelial growth factor receptor, XL184 Cabozantinib, PLC phospholipase C, IP3 inositol trisphosphate, Ca2+ intracellular free calcium.
