title: Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.
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 DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.
authors.affiliation: Department of Genome-based Drug Discovery, Graduation School of Biomedical Sciences, Nagasaki University.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakubo
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Mori
authors.forename: Keiro
authors.initials: K
authors.lastname: Shirotani
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000201:enzymology / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D006247:Harmine / Q000494:pharmacology; D006801:Humans; D015260:Neprilysin / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D006247:Harmine; D015260:Neprilysin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D014443:Tyrosine; D000097603:Dyrk Kinases; C545487:APP protein, human