Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease |
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Authors: | Ryoo Soo-Ryoon Cho Hyun-Jeong Lee Hye-Won Jeong Hey Kyeong Radnaabazar Chinzorig Kim Yeun-Soo Kim Min-Jeong Son Mi-Young Seo Hyemyung Chung Sul-Hee Song Woo-Joo |
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Affiliation: | Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan, South Korea; Division of Molecular and Life Sciences, College of Sciences and Technology, Hanyang University, Ansan-Si, Gyeonggi-Do, South Korea |
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Abstract: | Most individuals with Down Syndrome (DS) show an early-onset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode β-amyloid (Aβ) precursor protein ( APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A ( DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Aβ are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over-expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP. |
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Keywords: | Alzheimer's disease APP β-amyloid Down syndrome DYRK1A phosphorylation |
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