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

Mar 3, 2017Biological & pharmaceutical bulletin

Reduced Neprilysin Levels Linked to DYRK1A Activity in Cells from Down Syndrome

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Abstract

Neprilysin, a major enzyme that breaks down amyloid-β, is downregulated in fibroblasts from Down syndrome patients compared to those from healthy individuals.

Aβ accumulation is associated with the onset of Alzheimer's disease, with familial mutations significantly increasing Aβ production.
The Swedish mutation of amyloid precursor protein (APP) leads to a six-fold increase in Aβ production in cultured cells.
Down syndrome patients exhibit Alzheimer's-like pathologies at earlier ages due to a 1.5-fold increase in Aβ production from elevated APP gene expression.
Neprilysin downregulation in Down syndrome fibroblasts may contribute to accelerated Alzheimer's disease pathogenesis.
Inhibition of DYRK1A can upregulate neprilysin levels in fibroblasts, suggesting a potential therapeutic target.

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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.

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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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