Evaluation of exhaust air dust polymerase chain reaction as a supplement method for soiled bedding sentinel monitoring in specific pathogen free mouse facility using two different individually ventilated cage racks.

Health monitoring is essential for ensuring animal health and reliable research results. Each animal facility should establish adequate health monitoring methods, and microbiological quality control should be implemented through regular health surveillance. Recently, specific pathogen free (SPF) mice have been housed in individually ventilated cage (IVC) racks in the majority of mouse facilities globally, and health monitoring is implemented using a soiled bedding sentinel (SBS). Even though SBS monitoring is a standard method, it has a limitation in that some pathogens are not sufficiently transmitted to the sentinel housed in the IVC. The exhaust air dust polymerase chain reaction (EAD PCR) method has been reported to be a reliable complementary method to SBS monitoring based on research findings. In Korea, health monitoring programs using EAD PCR have not yet been applied to laboratory animal facilities. The microbiological status of mouse colonies housed in the two IVC racks was compared using SBS and EAD PCR monitoring in our SPF mouse facility. Except for Helicobacter spp. and Staphylococcus aureus, the detection of 16 pathogens did not differ between the two methods. In the detection of Helicobacter spp., EAD PCR was found to be more sensitive than SBS. Helicobacter spp. were not found by SBS, whereas four S. aureus positive samples were detected by either SBS or EAD PCR test. According to our findings, EAD PCR can be used as a supplement to SBS monitoring. Moreover, EAD PCR can reduce the number of animals used, making it a 3R (Replacement, Reduction, Refinement)-consistent method.

Identification of the responsible proteins for increased selenium bioavailability in the brain of transgenic rats overexpressing selenoprotein M.

The present study was conducted to investigate whether the high antioxidant activity induced by selenium (Sel) treatment and selenoprotein M (SelM) overexpression affected the protein profile of the brain cortex. To accomplish this, the changes in global protein expression were measured in transgenic (Tg) rats expressing human SelM (CMV/hSelM) and non­Tg rats using two-dimensional electrophoresis (2-DE). The results revealed that: ⅰ) CMV/hSelM Tg rats showed a high level of enzyme activity for antioxidant protein in the brain cortex compared to non-Tg rats; ⅱ) the high activity of these enzymes induced a decrease in total antioxidant concentration and γ-secretase activity in CMV/hSelM Tg rats; ⅲ) five proteins were upregulated and three were downregulated by SelM overexpression; ⅳ) among the five upregulated proteins, two associated with creatine kinase B-type (B-CK) and E3 ubiquitin-protein ligase RING1 (RING finger protein 1) were further increased in the two groups following Sel treatment, whereas synaptotagmin-15 (SytXV), eukaryotic translation initiation factor 4H (eIF-4H) and lactate dehydrogenase B (LDH-B) were increased or decreased under the same conditions; ⅴ) the three downregulated proteins did not induce a significant change in expression following Sel treatment; and ⅵ) the protein expression level alterations of the two selected spots (B-CK and SytXV) identified by 2-DE were extremely similar to the results from western blot analysis. Overall, the results of the present study provide primary novel biological evidence that new functional protein groups and individual proteins in the brain cortex of CMV/hSelM Tg rats are associated with Sel biology, including the response to Sel treatment and SelM overexpression.

Proteomic analysis of kidneys from selenoprotein M transgenic rats in response to increased bioability of selenium.

BACKGROUND: To characterize changes in global protein expression in kidneys of transgenic rats overexpressing human selenoprotein M (SelM) in response to increased bioabivility of selenium (Sel), total proteins extracted from kidneys of 10-week-old CMV/hSelM Tg and wild-type rats were separated by 2-dimensional gel electrophoresis and measured for changes in expression. RESULTS: Ten and three proteins showing high antioxidant enzymatic activity were up- and down-regulated, respectively, in SelM-overexpressing CMV/hSelM Tg rats compared to controls based on an arbitrary 2-fold difference. Up-regulated proteins included LAP3, BAIAP2L1, CRP2, CD73 antigen, PDGF D, KIAA143 homolog, PRPPS-AP2, ZFP313, HSP-60, and N-WASP, whereas down-regulated proteins included ALKDH3, rMCP-3, and STC-1. After Sel treatment, five of the up-regulated proteins were significantly increased in expression in wild-type rats, whereas there were no changes in CMV/hSelM Tg rats. Only two of the down-regulated proteins showed reduced expression in wild-type and Tg rats after Sel treatment. CONCLUSIONS: These results show the primary novel biological evidences that new functional protein groups and individual proteins in kidneys of Tg rats relate to Sel biology including the response to Sel treatment and SelM expression.

Nicastrin overexpression in transgenic mice induces aberrant behavior and APP processing.

Nicastrin (NCT) is a component of the presenilin protein complex, which is involved in the cleavage of ß-amyloid precursor protein (ßAPP) and Notch. The aim of this study was to determine the manner in which overexpression of wild-type human nicastrin (hNCTw) or mutant human nicastrin (hNCTm, D336A/Y337A) regulates brain functions and amyloid precusor protein (APP) processing. For this, we created transgenic (Tg) mice expressing neuron-specific enolase (NSE)-controlled hNCTw or hNCTm and measured their phenotypes as time passed. The NSE/hNCTw and NSE/hNCTm Tg groups exhibited greater behavioral dysfunction from 10 months of age than the non-Tg group, although their severities differed. Further, activity and component levels of the γ-secretase complex were significantly elevated in NSE/hNCTw Tg mice, expect for PEN-2. These alterations induced stimulation of APP processing, resulting in overproduction of Aß-42 peptide in the NSE/hNCTw Tg group, whereas the NSE/hNCTm Tg group showed a comparatively weaker effect. Furthermore, the highest expression levels of ß-secretase and NICD were observed in the NSE/hNCTw Tg group, similar to other phenotypes. Especially, a significances interference on the interaction between NCT and γ-secretase substrates was detected in NSE/hNCTm Tg groups compare with NSE/hNCTw Tg group. These results indicate that hNCTw overexpression in Tg mice promoted active assembly of the γ-secretase complex through modulation of APP processing and behavior, whereas the lesser effect in NSE/hNCTm Tg mice was due to reduced expression of hNCTm. These Tg mice could be useful for the development and application of therapeutic drugs in an animal model of Alzheimer's disease.

Effects of Red Liriope platyphylla on NGF secretion ability, NGF receptor signaling pathway and γ-secretase components in NSE/hAPPsw transgenic mice expressing Alzheimer's Disease.

Liriope platyphylla (LP) has long been regarded as a curative herb for the treatment of diabetes, asthma, and neurodegenerative disorders. To examine the therapeutic effects of Red LP (RLP) manufactured by steaming process on neurodegenerative disorders, significant alteration of the key factors influencing Alzheimer's Disease (AD) was detected in NSE/hAPPsw transgenic (Tg) mice after RLP treatment. The concentration of nerve growth factor (NGF) in serum increased in RLP-treated NSE/hAPPsw Tg mice compared with vehicle-treated Tg mice. However, downstream effectors of the NGF receptor signaling pathway, including TrkA and p75(NTR) proteins, were suppressed in RLP-treated NSE/hAPPsw Tg mice. Especially, Tg mice showed decreased levels of TrkA, p75(NTR), and RhoA expression. Production of Aß-42 peptides was lower in RLP-treated NSE/hAPPsw Tg mice than in vehicle-treated Tg mice. Further, analysis of γ-secretase components showed that Aß-42 peptide expression was downregulated. Of the four components, the expression of APH-1 and Nicastrin (NCT) decreased in RLP-treated NSE/hAPPsw Tg mice, whereas expression of PS-2 and Pen-2 was maintained or increased within the same group. Overall, these results suggest that RLP can help relieve neurodegenerative diseases, especially AD, through upregulation of NGF secretion ability, activation of NGF signaling pathway, downregulation of Aß-42 peptide deposition, and alteration of γ-secretase components.

Aqueous extract of Liriope platyphylla, a traditional Chinese medicine, significantly inhibits abdominal fat accumulation and improves glucose regulation in OLETF type II diabetes model rats.

Liriope platyphylla is a medical herb that has long been used in Korea and China to treat cough, sputum, neurodegenerative disorders, obesity, and diabetes. The aims of this study were to determine the antidiabetic and antiobesity effects of aqueous extract of L. platyphylla (AEtLP) through glucose and lipid regulation in both pre-diabetes and obesity stage of type II diabetes model. Two concentrations of AEtLP were orally administrated to OLETF (Otsuka Long-Evans Tokushima Fatty) rats once a day for 2 weeks, after which changes in glucose metabolism and fat accumulation were measured. Abdominal fat mass dramatically decreased in AEtLP-treated OLETF rats, whereas glucose concentration slightly decreased in all AEtLP-treated rats. However, compared to vehicle-treated OLETF rats, only AEtLP10 (10% concentration)-treated OLETF rats displayed significant induction of insulin production, whereas AEtLP5 (5% concentration)-treated OLETF rats showed a lower level of insulin. Although serum adiponectin level increased in only AEtLP5-treated rats, significant alteration of lipid concentration was detected in AEtLP5-treated OLETF rats. Expression of Glut-1 decreased in all AEtLP-treated rats, whereas Akt phosphorylation increased only in AEtLP10-treated OLETF rats. Furthermore, the pattern of Glut-3 expression was very similar with that of Glut-1 expression, which roughly corresponded with the phosphorylation of c-Jun N-teminal kinase (JNK) and p38 in the mitogen-activated protein kinase pathway. Therefore, these findings suggest that AEtLP should be considered as a therapeutic candidate during pre-diabetes and obesity stage capable of inducing insulin secretion from pancreatic ß-cells, glucose uptake in liver cells, as well as a decrease in fat and lipid accumulation.

Differential effects of the steaming time and frequency for manufactured red Liriope platyphylla on nerve growth factor secretion ability, nerve growth factor receptor signaling pathway and regulation of calcium concentration.

The herb Liriope platyphylla (LP) has been considered to have curative properties for diabetes, asthma and neurodegenerative disorders. To examine the effects of steaming time and frequency of manufactured red LP (RLP) on the nerve growth factor (NGF) secretion ability and NGF receptor signaling pathway, the NGF concentration, cell differentiation, NGF signaling pathway and calcium concentration were analyzed in neuronal cells treated with several types of LPs manufactured under different conditions. The maximum NGF secretion was observed in B35 cells treated with 50 µg/ml LP extract steamed for 9 h (9-SLP) and with two repeated steps (3 h steaming and 24 h air-dried) carried out 7 times (7-SALP). No significant changes in viability were detected in any of the cells treated with the various LPs, with the exception of 0-SLP and 0-SALP. In addition, PC12 cell differentiation was induced by treatment with the NGF-containing conditional medium (CM) collected from the RLP-treated cells. The levels of TrkA and extracellular signal-regulated kinase (ERK) phosphorylation in the high affinity NGF receptor signaling pathway were significantly higher in the cells treated with 3-SLP or 1-SALP/3-SALP CM compared with those treated with the vehicle CM. In the low affinity NGF receptor pathway, the expression levels of most components were higher in the 9-, 15- and 24-SALP CM-treated cells compared with the vehicle CM-treated cells. However, this level was significantly altered in cells treated with 3-SALP CM. Furthermore, an examination of the RLP function on calcium regulation revealed that only the LP- or RLP-treated cells exhibited changes in intracellular and extracellular calcium levels. RLP induced a significant decrease in the intracellular calcium levels and an increase in the extracellular calcium levels. These results suggest the possibility that steaming-processed LP may aid in the relief of neurodegenerative diseases through the NGF secretion ability and NGF signaling pathway.

Red Liriope platyphylla contains a large amount of polyphenolic compounds which stimulate insulin secretion and suppress fatty liver formation through the regulation of fatty acid oxidation in OLETF rats.

Red Liriope platyphylla (RLP) manufactured by two repeated steps (steaming and drying) stimulates the insulin secretion ability and glucose receptor signaling pathway in an animal model for type I diabetes. This study examined the levels of glucose and lipid metabolism-related factors in a useful animal model for type II diabetes with obesity following RLP treatment for 3 weeks to determine if RLP treatment affects the glucose concentration, insulin secretion and fatty acid oxidation. The following results were obtained: i) RLP contained a large amount of polyphenolic compounds; ii) insulin secretion was induced in RLP-treated OLETF rats, although there were no significant differences in body weight, glucose tolerance test and glucose concentration; iii) the RLP-treated OLETF rats showed a significant increase in adiponectin concentration but the concentration of triglyceride and LDL decreased compared to the vehicle-treated rats; iv) although the abdominal fat mass and adipocyte size did not change with RLP treatment, expression of the adipocyte marker genes and ß-oxidation genes in fat tissue was recovered to the level of the LETO rats; v) fatty liver formation was reduced dramatically in the liver of the RLP-treated group compared to the vehicle-treated group; vi) the expression of adipocyte marker genes and the ß-oxidation gene in the liver tissue were generally similar to those of the abdominal fat but PPAR-γ showed a reverse pattern in the RLP- and vehicle-treated OLETF rats. These results suggest that RLP may stimulate insulin secretion and a decrease in lipid in serum, and may also suppress fatty liver formation through the regulation of fatty acid oxidation. The data presented here highlight the possibility that RLP can be considered a candidate for the prevention or alleviation of obesity-related diseases.

Altered expression of γ-secretase components in animal model of major depressive disorder induced by reserpine administration.

Altered expression of neurotrophic factors as well as neuroinflammation is commonly associated with Major depressive disorder (MDD) and Alzheimer's disease (AD). To investigate whether or not reserpine-induced MDD affects the expression of AD-related proteins, the expression of γ-secretase components and substrate were measured in brains of ICR mice following reserpine treatment for 15 days. In active avoidance test, total response time and peak slightly increased in the 2 mg/kg reserpine (RSP2)-treated group compared to vehicle-treated group (P<0.05). Expression and phosphorylation of MKP-1, which is a key factor in MDD pathology, were both higher in the RSP2-treated group than the vehicle- and 1 mg/kg reserpine (RSP1)-treated groups (P<0.02). Furthermore, full-length expression of amyloid precursor protein (APP) was enhanced in the RSP1 and RSP2-treated groups compared to the vehicle-treated group, whereas expression of γ-secretase components decreased (P<0.03). Among the three components of the γ-secretase complex, nicastrin protein underwent the largest decrease in expression, as detected by Western blotting (P<0.03). Therefore, the data presented here provide additional evidence about the pathological correlation between MDD and AD.

Monitoring of antibiotic resistance in bacteria isolated from laboratory animals.

The drug resistance of microorganisms isolated from laboratory animals never treated with antibiotics is being reported consistently, while the number of laboratory animals used in medicine, pharmacy, veterinary medicine, agriculture, nutrition, and environmental and health science has increased rapidly in Korea. Therefore, this study examined the development of antimicrobial resistance in bacteria isolated from laboratory animals bred in Korea. A total of 443 isolates (7 species) containing 5 Sphingomonas paucimobilis, 206 Escherichia coli, 60 Staphylococcus aureus, 15 Staphylococcus epidermidis, 77 Enterococcus faecalis, 27 Citrobacter freundii, 35 Acinetobacter baumannii were collected from the nose, intestine, bronchus and reproductive organs of ICR mice and SD rats. Of these species, Acinetobacter baumannii and Enterococcus faecalis showed significant antimicrobial resistance according to the minimum inhibition concentration (MIC) in E-test. In case of Acinetobacter baumannii, several isolates showed MIC values 16-128 µg/mL for cefazolin and cefoxitin, and higher resistance (128-512 µg/mL) to nitrofurantoin than that of standard type. Resistance to cefazolin, cefoxitin and nitrofurantoin was detected in 17.14, 20.00, and 8.57% of the Acinetobacter baumannii isolates, respectively. In addition, 44.1% of the Enterococcus faecalis isolates collected from the laboratory animals were resistant to oxacillin concentration of 16-32 µg/mL range, while MIC value of standard type was below oxacillin concentration of 6 µg/mL. These results suggest that in rodent species of laboratory animals, Acinetobacter baumannii are resistance to cefazolin, cefoxitin and nitrofurantoin, whereas those of Enterococcus faecalis were resistance to oxacillin.

Overexpression of Insulin Degrading Enzyme could Greatly Contribute to Insulin Down-regulation Induced by Short-Term Swimming Exercise.

Exercise training is highly correlated with the reduced glucose-stimulated insulin secretion (GSIS), although it enhanced insulin sensitivity, glucose uptake and glucose transporter expression to reduce severity of diabetic symptoms. This study investigated the impact of short-term swimming exercise on insulin regulation in the Goto-Kakizaki (GK) rat as a non-obese model of non-insulin-dependent diabetes mellitus. Wistar (W/S) and GK rats were trained 2 hours daily with the swimming exercise for 4 weeks, and then the changes in the metabolism of insulin and glucose were assessed. Body weight was markedly decreased in the exercised GK rats compare to their non-exercised counterpart, while W/S rats did not show any exercise-related changes. Glucose concentration was not changed by exercise, although impaired glucose tolerance was improved in GK rats 120 min after glucose injection. However, insulin concentration was decreased by swimming exercise as in the decrease of GSIS after running exercise. To identify the other cause for exercise-induced insulin down-regulation, the changes in the levels of key factors involved in insulin production (C-peptide) and clearance (insulin-degrading enzyme; IDE) were measured in W/S and GK rats. The C-peptide level was maintained while IDE expression increased markedly. Therefore, these results showed that insulin down-regulation induced by short-term swimming exercise likely attributes to enhanced insulin clearance via IDE over-expression than by altered insulin production.

Effects of Steaming Time and Frequency for Manufactured Red Liriope platyphylla on the Insulin Secretion Ability and Insulin Receptor Signaling Pathway.

In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9-SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may contribute to the relief of diabetes symptoms and should be regarded as an excellent candidate for a diabetes treatment.

Pen-2 overexpression induces Aß-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice.

Pen-2 is a key regulator of the γ-secretase complex, which is involved in the production of the amyloid ß (Aß)-42 peptides, which ultimately lead to Alzheimer's disease (AD). While Pen-2 has been studied in vitro, Pen-2 function in vivo in the brains of transgenic (Tg) mice overexpressing human Pen-2 (hPen-2) protein has not been studied. This study aimed to determine whether Pen-2 overexpression could regulate the AD-like phenotypes in Tg mice. NSE/hPen-2 Tg mice were produced by the microinjection of the NSE/hPen-2 gene into the pronucleus of fertilized eggs. The expression of the hPen-2 gene under the control of the NSE promoter was successfully detected only in the brain and kidney tissue of NSE/hPen-2 Tg mice. Also, 12-month-old NSE/hPen-2 Tg mice displayed behavioral dysfunction in the water maze test, motor activity and feeding behavior dysfunction in food intake/water intake/motor activity monitoring system. In addition, tissue samples displayed dense staining with antibody to the Aß-42 peptide. Furthermore, NSE/hPen-2 Tg mice exhibiting feeding behavior dysfunction were significantly more apt to display symptoms related to diabetes and obesity. These results suggest that Pen-2 overexpression in NSE/hPen-2 Tg mice may induce all the AD-like phenotypes, including behavioral deficits, motor activity and feeding behavior dysfunction, Aß-42 peptide deposition and chronic disease induction.

Aß-42 deposition significantly increases the insolubility of synaptophysin in the brains of hAPPsw/hPS2m double transgenic mice.

Synaptophysin is a synaptic vesicle glycoprotein involved in the regulation process for neurotransmitter release, which is distributed throughout neuroendocrine cells and all neurons in the brain and spinal cord. In an effort to determine whether amyloid ß (Aß)-42 peptides could influence the quantity and biochemical properties of synaptophysin, alterations in the levels of the synaptophysin protein in various soluble fractions were detected in the brains of four genotypes of transgenic mice (Tg) including Non-Tg, neuron-specific enolase (NSE)-hPS2m, NSE-hAPPsw and hAPPsw/hPS2m double Tg mice. Among the four genotypes of Tg mice, the highest levels of Aß-42 peptides were noted in hAPPsw/hPS2m, followed by NSE-hAPPsw, NSE-hPS2m and Non-Tg mice. In the brains of these mice displaying different levels of Aß-42 peptides, the levels of soluble synaptophysin were reduced significantly only in the hAPPsw/hPS2m double Tg mice compared to the Non-Tg mice. However, immunohistochemical analysis revealed no differences in the levels of total synaptophysin protein between the neocortex and hippocampus of the four different genotypes of mice. Western blot analysis using four-step fractions with differing solubility revealed a marked decrease in synaptophysin levels in the Tris-buffer saline fraction of hAPPsw/hPS2m double Tg mice and a significant increase in the formic acid fraction, relative to the Non-Tg mice. The results obtained from our in vivo experiments in mice are identical to the results observed in SK-N-MC cells treated with 100 nM Aß-42 peptides. Therefore, our experiments collectively suggest that Aß-42 peptides may alter the solubility without changing the total amount of synaptophysin.

Differential regulation of the biosynthesis of glucose transporters by the PI3-K and MAPK pathways of insulin signaling by treatment with novel compounds from Liriope platyphylla.

The insulin signaling pathway, involving protein kinase B (PKB) and mitogen-activated protein kinase (MAPK), mediates the biological response to insulin and several growth factors and cytokines. To investigate the correlation between glucose transporter (Glut) biosynthesis and the insulin signaling pathway activated by novel compounds of Liriope platyphylla (LP9M80-H), alterations in Glut and key protein expression in the insulin signaling pathway were analyzed in the liver and brain of ICR mice treated with LP9M80-H. An in vitro assay showed that the highest level of insulin concentration was observed in the LP9M80-H-treated group, followed by the LP-H, LP-M, LP-E, and LP9M80-C-treated groups. Therefore, LP9M80-H was selected for use in studying the detailed mechanism of the insulin signaling pathway in animal systems. In an in vivo experiment, LP9M80-H induced a significant increase in glucose levels and a decrease of insulin concentration in the blood of mice, while their body weight remained constant over 5 days. The expression level of Glut-3 was down-regulated in the liver, or maintained at the same level in the brain of LP9MH80-H-treated mice. These changes corresponded to the phosphorylation of the p38 protein rather than to ERK and JNK in the MAPK signaling pathway. In addition, the expression level of Glut-1 increased significantly after LP9MH80-H treatment of both insulin target tissues in mice. Western blot analysis showed that Akt in the PI3-K pathway mainly participated in Glut-1 biosynthesis. Thus, these results suggest the possibility that the LP9M80-H-induced regulation of Glut-1 and Glut-3 biosynthesis may be mediated by the Akt and p38 MAPK signaling of the insulin signaling pathway in the liver and brain of mice.

Peroxiredoxin I regulates the component expression of γ-secretase complex causing the Alzheimer's disease.

Peroxiredoxin I (Prx I) is a member of the peroxiredoxins (Prxs) family, which are antioxidant enzymes that regulate various cellular process via intracellular oxidative signal pathways. In order to investigate the correlation between Prx I and the γ-secretase complex, which causes Alzheimer's disease (AD), the expression level of Prx I was firstly evaluated in an animal model for AD. NSE/hPen-2 transgenic (Tg) mice, which were used as animal model in this study, showed a high level of Pen-2 expression and accumulation of Aß-42 peptides in the hippocampus of brain. The expression level of Prx I was significantly higher on the mRNA and protein level in the brain of this model, while not change in Prx VI expression was observed. Furthermore, to verify the effect of Prx I on the γ-secretase components in vitro, the expression level of these components was analyzed in the Prx I transfectants. Of the components of the γ-secretase complex, the expression of PS-2 and Pen-2 was lower in the transfectants overexpressing Prx I compared to the vector transfectants. However, the expression of APP, NCT and APH-1 did not change in Prx I transfectants. Therefore, these results suggested that the expression of Prx I may be induced by the accumulation of Aß-42 peptides and the overexpression of Prx I in neuroblastoma cells may regulate the expression of γ-secretase components.

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.