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.
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 beta-amyloid (Abeta) 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 Abeta 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.
Ryoo
Soo-Ryoon
SR
Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan, South Korea.
Cho
Hyun-Jeong
HJ
Lee
Hye-Won
HW
Jeong
Hey Kyeong
HK
Radnaabazar
Chinzorig
C
Kim
Yeun-Soo
YS
Kim
Min-Jeong
MJ
Son
Mi-Young
MY
Seo
Hyemyung
H
Chung
Sul-Hee
SH
Song
Woo-Joo
WJ
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D051381:Rats; D013912:Threonine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D000097603:Dyrk Kinases
D016564:Amyloid beta-Protein Precursor; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D013912:Threonine; D014443:Tyrosine; D000097603:Dyrk Kinases