Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.

Amyloid-ß peptide (Aß) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aß production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects ß-secretase activity and increases Aß 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 Aß production. However, when comparing the causal relationship of Aß accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aß production alone. In this study, we found that neprilysin, a major Aß-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 Aß 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.

Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer's Disease.

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-ß 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.

[Prehepatectomy chemotherapy using hepatic artery infusion plus systemic chemotherapy for liver metastases from colorectal cancer].

The purpose of this study was to determine the efficacy of hepatic artery infusion (HAI) plus systemic chemotherapy (SYS) as the prehepatectomy chemotherapy for liver metastases from colorectal cancer. Clinicopathologic data were available for 117 patients who were treated with chemotherapy before liver surgery. Response rate of chemotherapy and frequency of liver resection after chemotherapy of patients treated with HAI/SYS (n=26; 65% and 96%, respectively) were higher than those treated with HAI alone (n=63; 41% and 70%) or SYS alone (n=28; 25% and 42%). Histological examination of adjacent nonneoplastic liver confirmed that severe sinusoidal dilatation was less frequent in HAI/SYS group than in SYS group, and moderate to severe steatosis was also less frequent in HAI/SYS group as compared to HAI group. The combination of regional HAI and systemic chemotherapy is an effective prehepatectomy regimen for the treatment of patients with aggressive liver metastases from colorectal cancer.

Solvothermal synthesis of n-type Bi2(SexTe1-x)3 nanoplates for high-performance thermoelectric thin films on flexible substrates.

To improve thermoelectric performance of materials, the utilization of low-dimensional materials with a multi-alloy system is a promising approach. We report on the enhanced thermoelectric properties of n-type Bi2(SexTe1-x)3 nanoplates using solvothermal synthesis by tuning the composition of selenium (Se). Variation of the Se composition within nanoplates is demonstrated using X-ray diffraction and electron probe microanalysis. The calculated lattice parameters closely followed Vegard's law. However, when the Se composition was extremely high, an impurity phase was observed. At a reduced Se composition, regular-hexagonal-shaped nanoplates with a size of approximately 500 nm were produced. When the Se composition was increased, the shape distribution became random with sizes more than 5 µm. To measure the thermoelectric properties, nanoplate thin films (NPTs) were formed on a flexible substrate using drop-casting, followed by thermal annealing. The resulting NPTs sufficiently adhered to the substrate during the bending condition. The electrical conductivity of the NPTs increased with an increase in the Se composition, but it rapidly decreased at an extremely high Se composition because of the presence of the impurity phase. As a result, the Bi2(SexTe1-x)3 NPTs exhibited the highest power factor of 4.1 µW/(cm∙K2) at a Se composition of x = 0.75. Therefore, it was demonstrated that the thermoelectric performance of Bi2(SexTe1-x)3 nanoplates can be improved by tuning the Se composition.

Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients.

Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary 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-ß peptide (Aß) 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 affinity for ß-secretase associated with a dramatic increase in Aß 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 Aß production and that there are factors exacerbating AD on chromosome 21. We therefore focused on dual-specificity 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 Aß-degrading enzyme in the brain, and phosphorylation at the NEP cytoplasmic domain. NEP activity was markedly reduced in fibroblasts derived from DS patients compared with that in fibroblasts 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 effective against AD not only in adults with DS but also in sporadic AD patients.