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

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Title: Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts
Authors: Kawakubo, Takashi / Mori, Ryotaro / Shirotani, Keiro / Iwata, Nobuhisa / Asai, Masashi
Issue Date: 1-Mar-2017
Publisher: 日本薬学会 / Pharmaceutical Society of Japan
Citation: Biological & Pharmaceutical Bulletin, 40(3), pp.327-333; 2017
Abstract: 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 DYRK1Amediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.
Keywords: Alzheimer's disease / Chromosome 21 / Down syndrome / Dual-specificity tyrosine phosphorylation-regulated kinase 1A / Neprilysin
URI: http://hdl.handle.net/10069/37474
ISSN: 09186158
DOI: 10.1248/bpb.b16-00825
Rights: © 2017 The Pharmaceutical Society of Japan
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/37474

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