Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1.5-fold higher than that in healthy people, thus causing a 1.5-fold increase in Aβ production. However, when comparing the causal relationship of Aβ accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aβ production alone. In this study, we found that neprilysin, a major Aβ-degrading enzyme, was downregulated in DS patient-derived fibroblasts, compared with healthy people-derived fibroblasts. Treatment with harmine, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is located in the DS critical region of chromosome 21, and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. These results suggest that a decrease in the Aβ catabolic rate may be, at least in part, one of the causes for accelerated AD-like pathogenesis in DS patients if a similar event occurs in the brains, and that neprilysin activity may be regulated directly or indirectly by DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.Key words Alzheimer's disease; chromosome 21; down syndrome; dual-specificity tyrosine phosphorylationregulated kinase 1A; neprilysin Alzheimer's disease (AD) brains are pathologically characterized by numerous senile plaques and neurofibrillary tangles, which consist of aggregation amyloid-β peptide (Aβ) and hyperphosphorylated tau, respectively, and prominent neuronal cell death. Aβ is generated from amyloid precursor protein (APP) by β-and γ-secretase-mediated sequential cleavages, followed by Aβ degradation by neprilysin (NEP). Aβ in healthy brains is maintained at a constant level by an equilibrium between the production and degradation rates. 1)An imbalance arising by a subtle change in either rate leads to Aβ accumulation.The Swedish double mutation (K670N/M671L) in APP, one of the most well-known mutations in familial AD, leads to a dramatic increase in total Aβ production.2,3) The average onset age of Swedish familial AD is around 55 years.4) On the other hand, Down syndrome (DS) is one of the most frequently occurring chromosomal abnormalities. 5,6) Approximately 95% of DS is caused by standard trisomy 21, which is an extra copy of chromosome 21. The remaining causes, chromosomal translocation and mosaicism, account for 1-5 and 1-2% of DS cases, respectively. DS patients have unique physical characteristics and suffer from various comp...

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...

Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neuroˆbrillary tangles by age 40 50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-b peptide (Ab) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high a‹nity for b-secretase associated with a dramatic increase in Ab production is about 55 years. This paradox indicates that there is a poor correlation between average ages of AD onset and the theoretical amount of Ab production and that there are factors exacerbating AD on chromosome 21. We therefore focused on dual-speciˆcity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), since overexpressing transgenic mice show AD-like brain pathology. The overexpression of DYRK1A caused suppression of the activity of neprilysin (NEP), which is a major Ab-degrading enzyme in the brain, and phosphorylation at the NEP cytoplasmic domain. NEP activity was markedly reduced inˆbroblasts derived from DS patients compared with that in broblasts derived from healthy controls. This impaired activity of NEP was rescued by DYRK1A inhibition. These results show that DYRK1A overexpression causes suppression of NEP activity through its phosphorylation in DS patients. Our results suggest that DYRK1A inhibitors could be eŠective against AD not only in adults with DS but also in sporadic AD patients.

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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.