DYRK1A-mediated Hyperphosphorylation of Tau

Abstract

Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21. Located on this chromosome is a gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the physiological significance of this phosphorylation, an analysis was made of the amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently generated. A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls. We further examined whether Dyrk1A phosphorylates other Tau residues that are implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule assembly. Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high. These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD. Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21. Located on this chromosome is a gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the physiological significance of this phosphorylation, an analysis was made of the amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently generated. A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls. We further examined whether Dyrk1A phosphorylates other Tau residues that are implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule assembly. Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high. These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD. Down syndrome (DS) 3The abbreviations used are: DS, Down syndrome; AD, Alzheimer disease; DYRK1A, dual specificity tyrosine phosphorylation-regulated kinase 1A; DYRK1A TG mice, transgenic mice that overexpress the human DYRK1A protein; NFTs, neurofibrillary tangles; PHFs, paired helical filaments; pS202, phospho-Ser-202-Tau; pT212, phospho-Thr-212-Tau; pS404, phospho-Ser-404-Tau; protein nomenclature, Dyrk1A for mouse protein and DYRK1A for human protein; WT, wild type; PBS, phosphate-buffered saline; MOPS, 4-morpholinepropanesulfonic acid; PIPES, 1,4-piperazinediethanesulfonic acid; siRNA, short interfering RNA; GFP, green fluorescent protein; JNK, c-Jun N-terminal kinase; APP, β-amyloid precursor protein; Aβ, β-amyloid. is the most common genetic disorder with a frequency of 1 in 800 live births, and it is caused by the presence of an extra copy of whole or part of human chromosome 21 (1Lejeune J. Gautier M. Turpin R. C. R. Hebd. Seances Acad. Sci. 1959; 248: 1721-1722PubMed Google Scholar, 2Jacobs P.A. Baikie A.G. Court Brown W.M. Strong J.A. Lancet. 1959; 1: 710Abstract PubMed Scopus (153) Google Scholar). DS patients suffer various symptoms, including congenital heart defects, immune and endocrine system defects, mental retardation, and early onset of Alzheimer disease (AD) (3Korenberg J.R. Chen X.N. Schipper R. Sun Z. Gonsky R. Gerwehr S. Carpenter N. Daumer C. Dignan P. Disteche C. Graham Jr., J.M. Hudgins L. McGillivray B. Miyazaki K. Ogasawara N. Park J.P. Pagon R. Pueschol S. Sack G. Say B. Schuffenhauer S. Soukup S. Yamanaka T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4997-5001Crossref PubMed Scopus (596) Google Scholar). Both DS and AD patients have pathological hall-marks, amyloid plaques and neurofibrillary tangles (NFTs) that are insoluble deposits made of proteins called β-amyloid (Aβ) and hyperphosphorylated Tau, respectively (4Grundke-Iqbal I. Iqbal K. Tung Y.C. Quinlan M. Wisniewski H.M. Binder L.I. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 4913-4917Crossref PubMed Scopus (2877) Google Scholar, 5Masters C.L. Simms G. Weinman N.A. Multhaup G. McDonald B.L. Beyreuther K. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 4245-4249Crossref PubMed Scopus (3668) Google Scholar, 6Burger P.C. Vogel F.S. Am. J. Pathol. 1973; 73: 457-476PubMed Google Scholar). Although an early onset AD in DS patients is not clearly understood, one potential mechanism is the presence of three chromosomal copies of β-amyloid precursor protein (APP) gene. However, the APP overexpression alone in mice does not show the endosome abnormalities observed in AD-like pathology (7Cataldo A.M. Petanceska S. Peterhoff C.M. Terio N.B. Epstein C.J. Villar A. Carlson E.J. Staufenbiel M. Nixon R.A. J. Neurosci. 2003; 23: 6788-6792Crossref PubMed Google Scholar), implying the necessity of additional genes on the chromosome 21 for a full spectrum of AD pathologies. NFTs found in AD are composed of paired helical filaments (PHFs), which are mainly composed of hyperphosphorylated Tau protein (8Selkoe D.J. Neuron. 1991; 6: 487-498Abstract Full Text PDF PubMed Scopus (2195) Google Scholar). To date, more than 30 phosphorylation sites and 7–10 mol of phosphates per mol of Tau have been observed in PHF-Tau (9Ksiezak-Reding H. Liu W.K. Yen S.H. Brain Res. 1992; 597: 209-219Crossref PubMed Scopus (191) Google Scholar, 10Kopke E. Tung Y.C. Shaikh S. Alonso A.C. Iqbal K. Grundke-Iqbal I. J. Biol. Chem. 1993; 268: 24374-24384Abstract Full Text PDF PubMed Google Scholar). Although Tau protein is phosphorylated in vitro by numerous kinases, it is unclear how many kinases actually phosphorylate Tau in vivo. Currently, only glycogen synthase kinase 3β (GSK3β), cyclin-dependent kinase 5, cAMP-dependent protein kinase A, and microtubule affinity-regulating kinase are known to modulate Tau phosphorylation in vivo at some level, either directly or indirectly (11Johnson G.V. Stoothoff W.H. J. Cell Sci. 2004; 117: 5721-5729Crossref PubMed Scopus (440) Google Scholar). The DYRK1A (dual specificity tyrosine (Y)-phosphorylation-regulated kinase 1A) gene is isolated from human chromosome 21 and encodes a protein kinase (12Kentrup H. Becker W. Heukelbach J. Wilmes A. Schurmann A. Huppertz C. Kainulainen H. Joost H.G. J. Biol. Chem. 1996; 271: 3488-3495Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 13Guimera J. Casas C. Pucharcos C. Solans A. Domenech A. Planas A.M. Ashley J. Lovett M. Estivill X. Pritchard M.A. Hum. Mol. Genet. 1996; 5: 1305-1310Crossref PubMed Scopus (186) Google Scholar, 14Shindoh N. Kudoh J. Maeda H. Yamaki A. Minoshima S. Shimizu Y. Shimizu N. Biochem. 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Neurosci. 2003; 17: 2277-2286Crossref PubMed Scopus (88) Google Scholar, 18Marti E. Altafaj X. Dierssen M. de la Luna S. Fotaki V. Alvarez M. Perez-Riba M. Ferrer I. Estivill X. Brain Res. 2003; 964: 250-263Crossref PubMed Scopus (97) Google Scholar), and mRNA in DS fetal brains has been shown to be overexpressed (19Guimera J. Casas C. Estivill X. Pritchard M. Genomics. 1999; 57: 407-418Crossref PubMed Scopus (145) Google Scholar). Dyrk1A has dual substrate specificities as follows: autophosphorylation on the tyrosine 321 residue for self-activation and phosphorylation of target proteins on serine/threonine residues with a preferred phosphorylation consensus motif of RPX(S/T)P (12Kentrup H. Becker W. Heukelbach J. Wilmes A. Schurmann A. Huppertz C. Kainulainen H. Joost H.G. J. Biol. Chem. 1996; 271: 3488-3495Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 20Himpel S. Tegge W. Frank R. Leder S. Joost H.G. Becker W. J. Biol. Chem. 2000; 275: 2431-2438Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 21Lochhead P.A. Sibbet G. Morrice N. Cleghon V. Cell. 2005; 121: 925-936Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). Dyrk1A potentially phosphorylates or interacts with several proteins, including transcription factors (NFATc, STAT3, Forkhead, CREB, and Gli1) and eukaryotic initiation factor 2Bϵ, Dynamin 1, cyclin L2, Hip-1, and α-synuclein, implying the multiple biological functions of DYRK1A (22Galceran J. de Graaf K. Tejedor F.J. Becker W. J. Neural Transm. Suppl. 2003; 67: 139-148Crossref PubMed Scopus (60) Google Scholar). Dyrk1A knock-out mice show a general delay in fetal development and are embryonic lethal, indicating the vital and nonredundant biological functions of Dyrk1A (23Fotaki V. Dierssen M. Alcantara S. Martinez S. Marti E. Casas C. Visa J. Soriano E. Estivill X. Arbones M.L. Mol. Cell. Biol. 2002; 22: 6636-6647Crossref PubMed Scopus (252) Google Scholar). We recently generated transgenic mice that overexpress human DYRK1A (DYRK1A TG mice) by introducing a bacterial artificial chromosome that only carries the human DYRK1A genomic DNA, including the endogenous promoter (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar). These DYRK1A TG mice show and to is in DS a that is with on the mouse Dyrk1A transgenic mice or the human genomic transgenic mice a chromosome 21 including DYRK1A on a artificial chromosome (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar, X. Dierssen M. C. Marti E. Visa J. J. M. J.R. J. C. Estivill X. Hum. Mol. Genet. PubMed Scopus Google Scholar, D.J. M. A.M. J. Genet. PubMed Scopus Google Scholar). it was reported that Dyrk1A phosphorylates Tau at Thr-212 in a residue that is phosphorylated in fetal Tau and hyperphosphorylated in Tau from AD brains P. Becker W. R. M. X. Biochem. J. PubMed Scopus Google Scholar). this we the physiological significance of this phosphorylation using transgenic mice that overexpress human DYRK1A (DYRK1A TG was found that that Tau phosphorylation at Thr-212 is in DYRK1A TG Tau protein was also phosphorylated at Ser-202 and Ser-404 residues by Dyrk1A in and the of the phosphorylation at residues in DYRK1A TG These results that the overexpression of DYRK1A in DS brains to early onset of AD pathology the hyperphosphorylation of Tau. and mouse Dyrk1A and by in endogenous the Dyrk1A protein was with as by the Tau, and of Tau was from was from and was from for Tau and pT212, from and to the for three The was as (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar). with and with phosphate-buffered by in PBS, The brains at and of mouse brains as (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google and first with pT212, and with and with with an examined with a using of Brain and TG mice that overexpressed the human DYRK1A which was from the genomic DYRK1A on a bacterial artificial and as (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar). in with by the for the and of brain by in a in a and 1 The protein was using the by and by with and Tau of was with a Tau Tau protein was for at 30 with the Dyrk1A in kinase MOPS, 1 and The on and by with Tau and protein was phosphorylated by either or Dyrk1A for as Tau proteins to microtubule as H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar). or phosphorylated Tau was with in 1 and 1 at was by of and was by the at and Cell Dyrk1A from a mouse brain and a human Tau The Dyrk1A was generated by the mouse with the was and by for was human embryonic cells with Dyrk1A and Tau using was used as a of for cells on with Dyrk1A and Tau cells with in PBS, with in PBS, and with for with the Tau, at for and with or for 1 by the using a was by the from the DYRK1A TG mice was with Tau or Dyrk1A for at in with and 1 The a with protein A the with in and the proteins to analysis for the in DYRK1A TG the DYRK1A and Tau phosphorylation at the Thr-212 residue in transgenic mice that overexpress human DYRK1A (DYRK1A TG mice) These DYRK1A TG mice copies of the mouse Dyrk1A gene and one copy of the human DYRK1A genomic DNA, and the human DYRK1A protein expression was by the endogenous The overexpression of DYRK1A in mice in a increase in kinase H. and J. in that phospho-Thr-212-Tau (pT212) expression was in the and of DYRK1A TG mice compared with 1, A and The increase in pT212 was observed in the of the and the of the DYRK1A overexpression was observed (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar). The results by analysis of brain from the of DYRK1A TG mice and with Tau, the amounts of pT212 in the DYRK1A TG mice by to The that phosphorylation of Tau at Thr-212 was in and that overexpression of DYRK1A is to Tau phosphorylation in vivo. Phosphorylation of Tau at Ser-202 and Ser-404 by it was reported that Dyrk1A phosphorylates substrate proteins at when is at the S. Tegge W. Frank R. Leder S. Joost H.G. Becker W. J. Biol. Chem. 2000; 275: 2431-2438Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). of the of Tau the presence of multiple serine/threonine residues by To further the role of Dyrk1A in Tau we examined whether this kinase phosphorylates Tau in vitro at other residues that are implicated in in AD, as Ser-202 and Ser-404 residues A. 2002; PubMed Scopus Google Scholar). The mouse Dyrk1A proteins and expressed in E. and as The human Tau was in the presence or of and the was to Phosphorylation of Ser-202 and Ser-404 was with phospho-Ser-202-Tau and phospho-Ser-404-Tau in the presence of Tau and Dyrk1A the and to a protein that to Tau on the that Dyrk1A phosphorylate the Ser-202 and Ser-404 residues of Tau directly in vitro. The phosphorylation of Tau by Dyrk1A not from E. kinase Dyrk1A as the Tau protein was phosphorylated only by the Dyrk1A and not by the The Dyrk1A on the of of the the autophosphorylation for kinase and the and proteins with for the not phosphorylation by Dyrk1A in mammalian A, cells with or a to by for the Tau, and cells with human Tau, mouse and The of and Tau examined by was used as a for by with Tau in the or presence of or The was used as an for the and The was used as an for the pT212 of by Tau is known that hyperphosphorylated Tau microtubule Tau and the We examined the to which Tau phosphorylation by Dyrk1A the ability of Tau in microtubule assembly. Phosphorylation of Tau by Dyrk1A strongly inhibited microtubule for of the with Tau phosphorylated by Dyrk1A was inhibited by when compared with that of The of was with that of a known Tau kinase that phosphorylates several Tau residues H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar). The strong of the microtubule in the presence of Dyrk1A that Dyrk1A potentially phosphorylates multiple residues in Tau. Tau Phosphorylation by the Dyrk1A in determine whether Dyrk1A phosphorylates Tau on and Thr-212 in a analysis was with of human embryonic cells that been with a Tau expression either in the presence or of a mouse Dyrk1A or Although the amounts of Tau the amounts of pS202, pT212, and strongly in cells Dyrk1A WT, not Dyrk1A indicating that Tau is phosphorylated by Dyrk1A in The and Ser-404 of Tau phosphorylated in the of mouse potentially on of the presence of endogenous Dyrk1A and other kinases, including H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar). a of kinase of Dyrk1A by with endogenous Dyrk1A in resulting in further of Tau phosphorylation, compared with that of To the cells with Dyrk1A with the mouse Dyrk1A and human Tau. A was used as a of Dyrk1A strongly inhibited expression of the of pS202, pT212, and also Dyrk1A not Tau expression that Dyrk1A phosphorylates Tau on and Ser-404 in vivo. of was demonstrated by the that the in an of mouse brain was only when the was with the not with the or the in the of and in the and of DYRK1A TG determine the physiological significance of Tau phosphorylation at the Ser-202 and Ser-404 DYRK1A TG mice with and that and in the and of DYRK1A TG mice to Strong observed in the of the or of the in DYRK1A TG mice to of in pS202, pT212, and also observed in in the and in the of DYRK1A TG mice 1A and The results by analysis of brain from the or of DYRK1A TG mice and that with Tau, the amounts of and in the of DYRK1A TG mice by and to that of respectively with Tau, the amounts of and in the of DYRK1A TG mice also by and to that of respectively results that phosphorylation of Tau at Ser-202 and Ser-404 is enhanced when the amount of DYRK1A is that overexpression of DYRK1A is to Tau hyperphosphorylation in vivo. of Dyrk1A with determine whether Tau is phosphorylated the with the brain of DYRK1A TG mice with shown in of Tau to of indicating that Dyrk1A interacts with Tau in DYRK1A TG with also an Dyrk1A and Tau as shown in We show that Tau residues at and Ser-404 are phosphorylated by Dyrk1A in vitro and in vivo and that amounts are in the brains of DYRK1A TG the first in vivo evidence of a physiological role for DYRK1A in Tau a that is known to be for the of NFTs in AD. transgenic mice show overexpression of Dyrk1A at the protein (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google and increase in Dyrk1A kinase compared with of littermate controls. a increase in the Dyrk1A kinase TG mice provide a of Down syndrome for the of Dyrk1A in vivo. of the DYRK1A protein in the of DS brains was by when compared with age-matched overexpression of DYRK1A in DS brains, resulting from of the DYRK1A gene on human chromosome early onset of AD pathology the hyperphosphorylation of Tau A that DYRK1A is also in the and of AD patients I. M. B. Martinez de M. Marti E. J. Dierssen M. 2005; PubMed Scopus Google Scholar), a role for DYRK1A in AD Strong of in the of the and of the in DYRK1A TG mice are with from that in AD and other hyperphosphorylated Tau is from the to the and E. H. 1994; PubMed Scopus Google Scholar). The presence of NFTs in DYRK1A TG mice brain was not using the of Neurosci. and Acad. Sci. Google Scholar), either the mice not for development of NFTs or Tau hyperphosphorylation alone is not for the of NFTs not it be to determine whether the in Tau phosphorylation observed in DYRK1A TG mice the of NFTs, either in DYRK1A mice or when are with mouse that Phosphorylation of of Tau PubMed Scopus Google Scholar), which and of Tau from to with this, Tau phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule the Tau hyperphosphorylation which in the and to the of NFTs E. H. 1994; PubMed Scopus Google Scholar). has been reported that phosphorylation at Ser-202 Tau and that phosphorylation at Ser-202 and not only also Sun Brain Res. Mol. Brain Res. 2005; PubMed Scopus Google Scholar). analysis of at the Thr-212 residue of Tau that this phosphorylation to filaments by the of M. J. 2005; PubMed Scopus Google Scholar). The which Tau phosphorylation at AD brain A. N. V. J. Binder L.I. J. Cell Sci. 2000; PubMed Google Scholar), and phosphorylation at has been reported to Tau and to the ability of Tau to H. G.V. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the in which Tau is phosphorylated by Dyrk1A at and suggest for DYRK1A in the of microtubule and in the of NFTs. has been reported that the of the ability of Tau to promote microtubule is to the of Tau phosphorylation H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar). Phosphorylation by Dyrk1A strongly the ability of Tau to promote microtubule The was with that of which potentially phosphorylates Tau residues P. Becker W. R. M. X. Biochem. J. PubMed Scopus Google Scholar). it is that in to the three phosphorylated pS202, pT212, and pS404, examined additional Tau residues be phosphorylated by that potential phosphorylation sites of Tau in DYRK1A TG mice not the DYRK1A and other Tau phosphorylation sites to be to this a that DYRK1A phosphorylated only the Thr-212 residue in Tau H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar). that and the is of the of Dyrk1A was used to phosphorylate Tau in a H. C.J. H. P. M. J. 2004; PubMed Scopus Google Scholar), the Dyrk1A was used in this and H. M. J. PubMed Scopus Google reported that the phosphorylated Tau by Dyrk1A inhibited microtubule assembly. However, also used Dyrk1A and the was than we used the Dyrk1A and the was is that either a at the potentially the of Dyrk1A with Tau or that a of Dyrk1A is for with and for the phosphorylation of Tau. A that Tau is phosphorylated by Dyrk1A in vitro at the Thr-212 residue and that this phosphorylation Tau for phosphorylation by P. Becker W. R. M. X. Biochem. J. PubMed Scopus Google Scholar). However, Tau phosphorylation at Thr-212 was not in Dyrk1A transgenic mice in an analysis I. M. B. Martinez de M. Marti E. J. Dierssen M. 2005; PubMed Scopus Google Scholar). The the with Dyrk1A TG mice I. M. B. Martinez de M. Marti E. J. Dierssen M. 2005; PubMed Scopus Google and the DYRK1A TG mice used in this (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google have from the in the used for the of the transgenic The promoter was used to mouse Dyrk1A expression in transgenic mice X. Dierssen M. C. Marti E. Visa J. J. M. J.R. J. C. Estivill X. Hum. Mol. Genet. PubMed Scopus Google Scholar), the endogenous human promoter was used to expression of the human DYRK1A gene in the DYRK1A TG mice (24Ahn K.J. Jeong H.K. Choi Choi I. W.J. 22: PubMed Scopus Google Scholar). is also that the that the human and mouse Dyrk1A proteins to this The mechanism is for the of early onset of AD in DS DYRK1A is in the and of AD patients I. M. B. Martinez de M. Marti E. J. Dierssen M. 2005; PubMed Scopus Google Scholar), a role for DYRK1A in AD was recently found that Dyrk1A also phosphorylated APP at in vitro and in and it caused an increase in the amounts The amounts of DYRK1A in DS brains to the hyperphosphorylation of Tau and amounts of an enhanced phosphorylation of These to the early onset of AD in DS evidence that the plaques and NFTs are of disease are not the of AD, at the of and Tau phosphorylation be K. E. 2005; PubMed Scopus Google Scholar, K. J. T. J. L. M. A. M. M. E. C. M. J. C. A. M. B. M. 2005; PubMed Scopus Google Scholar, D.M. D.J. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, C. B. Grundke-Iqbal I. Iqbal K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, K. R. Carlson Am. J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar). the results we that DYRK1A as a potential target for the of AD in DS and AD We I. for of the and and Z. W. for