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Title: ダウン症患者における早期アルツハイマー病発症メカニズムの解明
Other Titles: Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients
Authors: Asai, Masashi / Kawakubo, Takashi / Mori, Ryotaro / Iwata, Nobuhisa
Issue Date: 1-Jul-2017
Publisher: 日本薬学会 / Pharmaceutical Society of Japan
Citation: YAKUGAKU ZASSHI, 137(7), pp.801-805; 2017
Abstract: 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-β peptide (Aβ) 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 β-secretase associated with a dramatic increase in Aβ 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 Aβ 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 Aβ-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.
Keywords: Alzheimer's disease / amyloid-β peptide / Down syndrome / dual-specificity tyrosine phosphorylationregulated kinase 1A / neprilysin
URI: http://hdl.handle.net/10069/37690
ISSN: 00316903
DOI: 10.1248/yakushi.16-00236-2
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/10069/37690

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