Malfunction of calcineurin-NFAT signaling pathway is associated to the development of Alzheimer's disease in adults with Down syndrome

Abstract

Down syndrome (DS), the most common genetic disorder, is mainly caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Vascular endothelial growth factor (VEGF) plays a central role in tumor development. VEGF and the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway regulates cancer metastasis. The Ca²⁺/calmodulin-dependent serine/threonine phosphatase calcineurin dephosphorylates NFAT in the cytoplasm, leading to its nuclear translocation and activation. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates NFAT in the nucleus, leading to its cytoplasmic translocation and inactivation. Calcineurin is negatively regulated by the DS critical region protein regulator of calcineurin 1 (RCAN1) in the cytoplasm. The genes for both DYRK1A and RCAN1 are located on chromosome 21. The calcineurin-NFAT signaling pathway is perturbed by the increased dosage of DYRK1A and RCAN1 in people with DS, and this disruption reduces the incidence of solid tumors in these patients. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in adults with DS.

Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein (APP). Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide (Aβ) levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.