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

• Published in: Journal of neurochemistry 2008-03, Vol.104 (5), p.1333-1344
• Main 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
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; APP; Biochemistry; Biological and medical sciences; Cell Line; Chromosome aberrations; Chromosomes; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Down syndrome; Down Syndrome - genetics; Down Syndrome - metabolism; Dyrk Kinases; DYRK1A; Gene Expression Regulation - physiology; Humans; Medical genetics; Medical sciences; Mice; Mice, Transgenic; Neurology; PC12 Cells; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - isolation & purification; Protein Serine-Threonine Kinases - physiology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - isolation & purification; Protein-Tyrosine Kinases - physiology; Rats; Rodents; Threonine - metabolism; Transgenic animals; Tyrosine - metabolism; β-amyloid
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.05075.x

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.