Asai Masashi, Kawakubo Takashi, Mori Ryotaro, Iwata Nobuhisa
Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University.
Yakugaku Zasshi. 2017;137(7):801-805. doi: 10.1248/yakushi.16-00236-2.
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.
唐氏综合征（DS）患者在40 - 50岁时会出现阿尔茨海默病（AD）的神经病理学特征，即形成老年斑和神经原纤维缠结。多年来一直认为，位于21号染色体上的淀粉样前体蛋白（APP）基因的1.5倍表达导致淀粉样β肽（Aβ）过量产生，从而导致DS成年患者早发性AD。然而，携带对β分泌酶具有高亲和力且与Aβ产生显著增加相关的瑞典突变的家族性AD的平均发病年龄约为55岁。这一矛盾表明，AD发病的平均年龄与理论上的Aβ产生量之间相关性较差，并且21号染色体上存在加剧AD的因素。因此，我们将重点放在双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）上，因为过表达转基因小鼠表现出类似AD的脑病理学特征。DYRK1A的过表达导致脑内主要的Aβ降解酶中性内肽酶（NEP）的活性受到抑制，并且NEP细胞质结构域发生磷酸化。与健康对照来源的成纤维细胞相比，DS患者来源的成纤维细胞中NEP活性明显降低。通过抑制DYRK1A可挽救这种受损的NEP活性。这些结果表明，在DS患者中，DYRK1A的过表达通过其磷酸化作用导致NEP活性受到抑制。我们的结果表明，DYRK1A抑制剂不仅对DS成年患者的AD有效，对散发性AD患者也可能有效。
