Down syndrome (DS), the most common genetic disorder, is 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. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. 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. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide 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.Key words Alzheimer's disease; Down syndrome; calcineurin; neprilysin; nuclear factor of activated T cell (NFAT); tau Down syndrome (DS) is the most frequent congenital chromosomal disorder, and is primarily caused by an extra copy of chromosome 21. The incidence of DS, approximately one in 600-800 live births, increases with maternal age.1,2) The characteristic physical features of the disease include a flattened face and nose, small head, ears and mouth, wide, short hands with short fingers, dry skin, and decreased or poor muscle tone. Children with DS are at increased risk of complications, including heart defects, hearing and vision problems, obesity, leukemia, and other conditions. 3-5) DS patients in middle age are more susceptible to the development of Alzheimer's disease (AD), 6,7) whereas most cancers are rare in people with DS, in whom overall cancer mortality is below 10% of that in the general population. 8)Vascular endothelial growth factor (VEGF) plays a central role in tumor development.9,10) VEGF and the calcineurinnuclear factor of activated T cells (NFAT) signaling pathway regulates cancer metastasis.9) The Ca 2+ /calmodulin-dependent serine/threonine phosphatase calcineurin dephosphorylates NFAT in the cytoplasm, leading to its nuclear translocation and activation.9,11,12) Dual specificity tyrosine-phosphorylationregulated kinase 1A (DYRK1A) phosphorylates NFAT in the nucleus, leading to its cytoplasmic translocation and inactivation.9,12) Calcineurin is negatively regulated by the DS critical region protein regulator of calcineurin 1 (RCAN1) in the cytoplasm. 9,12) 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 DS pa...

Islets from the same donor were transplanted to each pair and for each pair, one rat was treated with C5a inhibitory peptide (bolus: 4 mg/kg, continuous infusion: 0.42 mg/kg/hr for 3 days) in addition to a continuous intravenous infusion of gabexate mesilate (2 mg/kg/hr) 30 minutes prior to islet infusion and up to 1 hour after the infusion. The other recipient was injected with equivalent amount of saline and served as a control. Two rats were treated with the same dose of gabexate mesilate. The curative rate, the duration to normoglycemia, insulin amount in the liver of the recipients, and in vivo glucose tolerance tests were evaluated. Results: The curative rate was remarkably improved (100% vs. 33.3%, p=0.005) and the duration to normoglycemia in cured animals was signifi cantly shortened in treated group (12.2 }1.4 vs. 25.0 }0.0, p=0.039). Two rats only received the gabexate mesilate did not restore normoglycemia during the whole study period. No difference was observed between the groups in terms of glucose tolerance (AUC:p=0.85, Kg:p=0.35). However, insulin amount in the liver was considerably higher in treated group than that in control group (18.0 }3.2 vs. 12.0 }1.0 ng/IEQs p=0.14). Notably, the increase of body weight in the recipients was not affected by treatment (the increase rate of body weight: 128.6 }1.2% vs. 127.7 }3.3%, p=0.80), suggesting that C5a inhibitory peptide combined with the gabexate mesilate is considered to be free from the side effect. Conclusions: These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate, without side effects, to control the detrimental innate immune responses induced in clinical islet transplantation.

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 Ca 2+ /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.