Community-Based Aerobic Exercise Program for Primary Prevention of Cardiovascular Disease in Adults With Visual or Auditory Impairments: A Feasibility Study.

OBJECTIVE: To investigate the feasibility of a public health center-based aerobic and resistance training program for primary prevention of cardiovascular disease in people with visual, auditory, or physical/brain impairments. METHODS: The study included 25 adults aged >40 years who lived in Cheorwon-gun in South Korea, had a disability registered for visual, auditory, or physical/brain impairments under the Disability Welfare Act, and had either known cardiovascular disease or two or more risk factors for cardiovascular disease. The program comprised four education sessions and 12 weeks of customized aerobic and strengthening exercises performed twice a week at moderate intensity, with each exercise session lasting for 1 hour. The body mass index (BMI), percent body fat, 6-minute walk distance (6MWD), and 30-second sit-to-stand test results were measured at baseline and on program completion. RESULTS: Seventeen subjects (68%) completed the program. There were significant decreases in BMI and percent body fat (both p<0.05), with a significant increase in 30-second sit-to-stand strength (p<0.05) but no changes in the 6MWD. In subjects with visual or auditory impairments, BMI and percent body fat were significantly decreased after the program; however, there was no significant change in the results of the 30-second sit-to-stand strength test or the 6MWD. CONCLUSION: In people with disabilities, a 3-month community-based exercise program can decrease body mass index and percent body fat and increase sit-to-stand strength. The 30-second sit-to-stand test may be a useful measure of the strength and endurance of the lower extremities in people with disabilities.

A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition.

DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases.

Enhancement of BACE1 Activity by p25/Cdk5-Mediated Phosphorylation in Alzheimer's Disease.

The activity of beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is elevated during aging and in sporadic Alzheimer's disease (AD), but the underlying mechanisms of this change are not well understood. p25/Cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathogenesis of several neurodegenerative diseases, including AD. Here, we describe a potential mechanism by which BACE activity is increased in AD brains. First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. Then, we demonstrate that the level of phospho-BACE1 is increased in the brains of AD patients and in mammalian cells and transgenic mice that overexpress p25. Furthermore, the fraction of p25 prepared from iodixanol gradient centrifugation was unexpectedly protected by protease digestion, suggesting that p25/Cdk5-mediated BACE1 phosphorylation may occur in the lumen. These results reveal a link between p25 and BACE1 in AD brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation.

Phosphorylation and inactivation of glycogen synthase kinase 3ß (GSK3ß) by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A).

Glycogen synthase kinase 3ß (GSK3ß) participates in many cellular processes, and its dysregulation has been implicated in a wide range of diseases such as obesity, type 2 diabetes, cancer, and Alzheimer disease. Inactivation of GSK3ß by phosphorylation at specific residues is a primary mechanism by which this constitutively active kinase is controlled. However, the regulatory mechanism of GSK3ß is not fully understood. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) has multiple biological functions that occur as the result of phosphorylation of diverse proteins that are involved in metabolism, synaptic function, and neurodegeneration. Here we show that GSK3ß directly interacts with and is phosphorylated by Dyrk1A. Dyrk1A-mediated phosphorylation at the Thr(356) residue inhibits GSK3ß activity. Dyrk1A transgenic (TG) mice are lean and resistant to diet-induced obesity because of reduced fat mass, which shows an inverse correlation with the effect of GSK3ß on obesity. This result suggests a potential in vivo association between GSK3ß and Dyrk1A regarding the mechanism underlying obesity. The level of Thr(P)(356)-GSK3ß was higher in the white adipose tissue of Dyrk1A TG mice compared with control mice. GSK3ß activity was differentially regulated by phosphorylation at different sites in adipose tissue depending on the type of diet the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins, including peroxisome proliferator-activated receptor γ, in 3T3-L1 cells and in young Dyrk1A TG mice fed a chow diet. Taken together, these results reveal a novel regulatory mechanism for GSK3ß activity and indicate that overexpression of Dyrk1A may contribute to the obesity-resistant phenotype through phosphorylation and inactivation of GSK3ß.

Dyrk1A-mediated phosphorylation of RCAN1 promotes the formation of insoluble RCAN1 aggregates.

The mechanisms underlying aggregate formation in age-related neurodegenerative diseases remain not well understood. Here we investigated whether dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is involved in the formation of regulator of calcineurin 1 (RCAN1) aggregates. We show that RCAN1 self-associates and forms multimers, and that this process is promoted by the Dyrk1A-mediated phosphorylation of RCAN1 at the Thr(192) residue. Transgenic mice that overexpress the Dyrk1A exhibited lower levels of phospho-Thr(192)-RCAN1 in 10-month-old-group compared to littermate controls, when analyzed with soluble hippocampus lysates. These results suggest that the phosphorylation of RCAN1 by Dyrk1A stimulates the formation of insoluble aggregates upon aging.

Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals.

Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain (mnb) and the mammalian ortholog Dyrk1a, target genes of sNPF and NPY signaling, [corrected] regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, and [corrected] increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals.

Phosphorylation of Munc18-1 by Dyrk1A regulates its interaction with Syntaxin 1 and X11α.

Dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease in Down's syndrome patients. Dyrk1A plays a role in many cellular pathways through phosphorylation of diverse substrate proteins; however, its role in synaptic vesicle exocytosis is poorly understood. Munc18-1, a central regulator of neurotransmitter release, interacts with Syntaxin 1 and X11α. Syntaxin 1 is a key soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein involved in synaptic vesicle docking/fusion events, and X11α modulates amyloid precursor protein processing and ß amyloid generation. In this study, we demonstrate that Dyrk1A interacts with and phosphorylates Munc18-1 at the Thr(479) residue. The phosphorylation of Munc18-1 at Thr(479) by Dyrk1A stimulated binding of Munc18-1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho-Thr(479) -Munc18-1 were enhanced in the brains of transgenic mice over-expressing Dyrk1A protein, providing in vivo evidence of Munc18-1 phosphorylation by Dyrk1A. These results reveal a link between Munc18-1 and Dyrk1A in synaptic vesicle trafficking and amyloid precursor protein processing, suggesting that up-regulated Dyrk1A in Down's syndrome and Alzheimer's disease brains may contribute to some pathological features, including synaptic dysfunction and cognitive defect through abnormal phosphorylation of Munc18-1.

Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP.

Neural Wiskott-Aldrich syndrome protein (N-WASP) is involved in tight regulation of actin polymerization and dynamics. N-WASP activity is regulated by intramolecular interaction, binding to small GTPases and tyrosine phosphorylation. Here, we report on a novel regulatory mechanism; we demonstrate that N-WASP interacts with dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A). In vitro kinase assays indicate that Dyrk1A directly phosphorylates the GTPase-binding domain (GBD) of N-WASP at three sites (Thr196, Thr202 and Thr259). Phosphorylation of the GBD by Dyrk1A promotes the intramolecular interaction of the GBD and verprolin, cofilin and acidic (VCA) domains of N-WASP, and subsequently inhibits Arp2/3-complex-mediated actin polymerization. Overexpression of either Dyrk1A or a phospho-mimetic N-WASP mutant inhibits filopodia formation in COS-7 cells. By contrast, the knockdown of Dyrk1A expression or overexpression of a phospho-deficient N-WASP mutant promotes filopodia formation. Furthermore, the overexpression of a phospho-mimetic N-WASP mutant significantly inhibits dendritic spine formation in primary hippocampal neurons. These findings suggest that Dyrk1A negatively regulates actin filament assembly by phosphorylating N-WASP, which ultimately promotes the intramolecular interaction of its GBD and VCA domains. These results provide insight on the mechanisms contributing to diverse actin-based cellular processes such as cell migration, endocytosis and neuronal differentiation.

Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation.

Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3ß-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tau phosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS.

Overexpression of Dyrk1A causes the defects in synaptic vesicle endocytosis.

Trisomy 21-linked Dyrk1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) overexpression is implicated in pathogenic mechanisms underlying mental retardation in Down syndrome (DS). It is known to phosphorylate multiple substrates including endocytic proteins in vitro, but the functional consequence of Dyrk1A-mediated phosphorylation on endocytosis has never been investigated. Here, we show that overexpression of Dyrk1A causes defects in clathrin-mediated endocytosis and specifically, in the recruitment of endocytic proteins to clathrin-coated pits in fibroblasts. Synaptic vesicle endocytosis also significantly slowed down as a result of Dyrk1A overexpression in cultured hippocampal neurons. These effects are dependent on Dyrk1A kinase activity. The inhibitory effect of Dyrk1A on synaptic vesicle endocytosis was confirmed in neuronal cultures derived from transgenic mice overexpressing Dyrk1A at levels found in DS. Pharmacological blockade of Dyrk1A with epigallocatechin gallate rescued the endocytic phenotypes found in transgenic neurons. Together, our results suggest that aberrant Dyrk1A-mediated phosphorylation of the endocytic machinery perturbs synaptic vesicle endocytosis, which may contribute to synaptic dysfunctions and cognitive deficits associated with DS.

Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells.

Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e.g. p21(CIP1)) and impaired G(1)/G(0)-S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cell-derived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21(CIP1) as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21(CIP1) induction.

Dyrk1A-mediated phosphorylation of Presenilin 1: a functional link between Down syndrome and Alzheimer's disease.

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the γ-secretase complex in the generation of ß-amyloid (Aß), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Aß production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Aß is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr(354) and that this phosphorylation increases γ-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Aß pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.

Negative feedback Inhibition of NFATc1 by DYRK1A regulates bone homeostasis.

DYRK1A is a serine/threonine kinase that has been linked to mental retardation associated with Down syndrome. In the present report, we describe a previously unknown role for DYRK1A in bone homeostasis. The protein expression of DYRK1A increased during osteoclast differentiation. In vitro studies in osteoclasts revealed that DYRK1A inhibited osteoclastogenesis. Whereas DYRK1A phosphorylated and inhibited the osteoclastogenic transcription factor NFATc1, forced expression of NFATc1 induced DYRK1A expression, suggesting a negative feedback loop. Transgenic mice overexpressing DYRK1A by the extent of the increased gene dosage in Down syndrome exhibited significantly reduced bone mass despite the decreased osteoclastogenesis, which is reminiscent of osteoporotic bone phenotype in Down syndrome patients. In these mice, attenuated osteoblast differentiation and function in the presence of extra DYRK1A overrode the effect of impaired osteoclastogenesis. However, impeded osteoclastogenesis in DYRK1A transgenic mice was proven to be beneficial in protecting bone loss induced by inflammation or estrogen deficiency. These results provide novel insight into the role for DYRK1A in bone homeostasis as well as in bone destructive diseases, in which modulation of DYRK1A might be used as a strategy to treat unregulated bone resorption.

Function and regulation of Dyrk1A: towards understanding Down syndrome.

Down syndrome (DS) is associated with a variety of symptoms, such as incapacitating mental retardation and neurodegeneration (i.e., Alzheimer's disease), that prevent patients from leading fully independent lives. These phenotypes are a direct consequence of the overexpression of chromosome 21 genes, which are present in duplicate due to non-disjunction of chromosome 21. Accumulating data suggest that the chromosome 21 gene product, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1A), participates in the pathogenic mechanisms underlying the mental and other physical symptoms of DS. In this review, we summarize the evidence supporting a role for Dyrk1A in DS, especially DS pathogenesis. Recently, several natural and synthetic compounds have been identified as Dyrk1A inhibitors. Understanding the function and regulation of Dyrk1A may lead to the development of novel therapeutic agents aimed at treating DS.

QSAR analysis of pyrazolidine-3,5-diones derivatives as Dyrk1A inhibitors.

Individuals with Down syndrome (DS) suffer from mental retardation. Overexpression and the resulting increased specific activity of Dyrk1A kinase located on chromosome 21 cause a learning and memory deficit in Dyrk1A transgenic mice. To search for therapeutic agents with Dyrk1A inhibition activity, previously we obtained HCD160 as a new hit compound for Dyrk1A inhibition. In the present study, we synthesized 34 HCD160 derivatives to investigate the quantitative structure-activity relationship (QSAR). This analysis could provide important information for novel drug discovery for treatment of DS related learning and memory deficits.

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.

Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation.

Delta-catenin was first identified through its interaction with Presenilin-1 and has been implicated in the regulation of dendrogenesis and cognitive function. However, the molecular mechanisms by which delta-catenin promotes dendritic morphogenesis were unclear. In this study, we demonstrated delta-catenin interaction with p190RhoGEF, and the importance of Akt1-mediated phosphorylation at Thr-454 residue of delta-catenin in this interaction. We have also found that delta-catenin overexpression decreased the binding between p190RhoGEF and RhoA, and significantly lowered the levels of GTP-RhoA but not those of GTP-Rac1 and -Cdc42. Delta-catenin T454A, a defective form in p190RhoGEF binding, did not decrease the binding between p190RhoGEF and RhoA. Delta-catenin T454A also did not lower GTP-RhoA levels and failed to induce dendrite-like process formation in NIH 3T3 fibroblasts. Furthermore, delta-catenin T454A significantly reduced the length and number of mature mushroom shaped spines in primary hippocampal neurons. These results highlight signaling events in the regulation of delta-catenin-induced dendrogenesis and spine morphogenesis.

DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease.

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.

Putative therapeutic agents for the learning and memory deficits of people with Down syndrome.

Mental retardation is the most common and debilitating condition for individuals with Down syndrome (DS). The hyper-activation of DYRK1A by overexpression causes significant learning and memory deficits in DS-model mice. Thus far, no mechanism-based drug has been developed to address this. After a combination of in silico and in vitro screenings, two DYRK1A inhibitors were isolated that are active in a cell-based assay. Further optimization could lead to a novel drug discovery that could address DS learning and memory deficits.

DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects.

Among the various phenotypes seen in Down syndrome (DS), mental retardation is the most common and most debilitating condition suffered by individuals with DS. The DYRK1A gene on human chromosome 21q22.2 encodes a subfamily of protein kinases that displays dual substrate specificities and is known to play a critical role in neurodevelopment. To study DS mental retardation, we have generated transgenic mice that contain only one copy of the complete human DYRK1A gene in a bacterial artificial chromosome. The transgenic mice showed significant impairment in hippocampal-dependent memory tasks in a Morris water maze. Interestingly, we observed shifts in both long-term potentiation and long-term depression, which suggests a role for DYRK1A in bidirectional synaptic plasticity. These mice represent the most clinically relevant DYRK1A mouse model to date and provide us a valuable tool for the in vivo study of mechanisms that underlie the learning and memory deficit in DS.