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1.  The 12-15Lipoxygenase is a modulator of Alzheimer’s related tau pathology in vivo 
Aging cell  2013;12(6):10.1111/acel.12136.
Summary
12/15-Lipoxygenase (12/15LO) is a lipid-peroxidizing enzyme widely expressed in the central nervous system where it has been involved in the neurobiology of Alzheimer disease (AD) because it modulates Amyloid beta (Aβ) and APP processing. However, its biological effect on tau protein is unknown. We investigated the effect of 12/15LO on tau levels and metabolism in vivo and in vitro and the mechanism involved by using genetic and pharmacologic approaches. While no significant differences were observed in the levels of total tau for both groups, compared with controls, Tg2576 mice over-expressing 12/15LO had elevated levels of phosphorylated tau at two specific epitopes, Ser 202/Thr 205 and Ser 396. In vitro and in vivo studies show that 12/15LO modulates tau metabolism specifically via the cdk5 kinase pathway. Associated with these changes were biochemical markers of synaptic pathology. Finally, 12/15-LO-dependent alteration of tau metabolism was independent from an effect on Aβ. Our findings reveal a novel pathway by which 12/15LO modulates endogenous tau metabolism making this protein an appealing pharmacologic target for treatment of AD and related tauopathies.
doi:10.1111/acel.12136
PMCID: PMC3838477  PMID: 23862663
2.  Gene Knockout of 5-Lipoxygenase Rescues Synaptic Dysfunction and Improves Memory in the Triple-Transgenic Model of Alzheimer’s Disease 
Molecular psychiatry  2013;19(4):511-518.
The 5-Lipoxygenase (5LO) is upregulated in Alzheimer’s disease (AD), and in vivo modulates the amyloidotic phenotype of APP transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue we used a genetic and a pharmacologic approach by generating 3xTg mice deficient for 5LO, and administering 3xTg mice which a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life these mice had a significant reduction of Aβ and tau pathology.
Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this proetin as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.
doi:10.1038/mp.2013.23
PMCID: PMC3688674  PMID: 23478745
3.  The Influence of 5-Lipoxygenase on Alzheimer’s Disease-Related Tau Pathology: In Vivo and In Vitro Evidence 
Biological psychiatry  2013;74(5):321-328.
Background
Intracellular deposition of tau protein is a hallmark lesion of Alzheimer’s disease. Although it is known this event is secondary to excessive tau phosphorylation, the mechanisms involved remain unknown. We previously reported that the enzyme 5-Lipoxygenase (5LO) acts as a modulator of Aβ peptides formation in vivo, and here we investigate its influence on tau protein.
Methods
Tg2576 mice overexpressing neuronal 5LO were generated and its contribution to endogenous tau levels and metabolism investigated.
Results
Although no differences were noted in the levels of total tau for both groups, compared with controls, Tg2576 mice overexpressing 5LO had a significant increase in the phosphorylation state of tau at S396 and S396/S404, as recognized by the antibodies PHF-13 and PHF-1, respectively. By contrast, no phosphorylation changes were observed in other tau epitopes. This increase was associated with a significant elevation in cyclin dependent kinase-5 but not other kinases that have been involved in tau phosphorylation. Additionally, mice overexpressing 5LO had biochemical evidence of altered synaptic integrity because they manifested a reduction in PSD-95, synaptophysin and MAP2.
Conclusions
This study demonstrates a new role for 5LO in regulating endogenous tau metabolism in the central nervous system and supports the hypothesis that its pharmacologic inhibition could be beneficial for Alzheimer’s disease-related tau neuropathology.
doi:10.1016/j.biopsych.2012.12.012
PMCID: PMC3726558  PMID: 23352590
5-Lipoxygenase; Alzheimer’s disease; amyloid beta; cyclin dependent kinase-5; tau protein; transgenic mouse model
4.  5-Lipoxygenase Activating Protein Reduction Ameliorates Cognitive Deficit, Synaptic Dysfunction, and Neuropathology in a Mouse Model of Alzheimer’s Disease 
Biological psychiatry  2013;74(5):348-356.
Background
5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer’s disease (AD) with plaques and tangles (i.e., 3×Tg mice).
Methods
By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3×Tg mice.
Results
We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway.
Conclusions
Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.
doi:10.1016/j.biopsych.2013.04.009
PMCID: PMC3742720  PMID: 23683389
Amyloid beta; Alzheimer’s disease; behavior; FLAP protein; tau protein; transgenic mouse models
5.  Buckwheat Rutin Inhibits AngII-induced Cardiomyocyte Hypertrophy via Blockade of CaN-dependent Signal Pathway  
Buckwheat rutin has been found to be able to inhibit angiotensin II (AngII) - induced hypertrophy in cultured neonatal rat cardiomyocytes, but the mechanism remains uncertain. In this study, myocardial hypertrophy model was made by adding AngII to the medium of cardiac myocytes of neonatal rats; meanwhile, different concentrations of buckwheat rutin were applied to observe their effects. Intracellular Ca2+ level was detected by Hitachi - 850 fluorospectrophotometer, calcineurin (CaN) activity was measured by colorimetric method, the expression of CaN protein was observed with immunocytochemistry, and the proto - oncogene c - fos mRNA expression was assessed with reverse transcription polymerase chain reaction (RT - PCR). Compared with control group, AngII could greatly stimulate the increase of intracellular Ca2+ level, the activities and protein expression of cardiomyocytes CaN, and the expression of proto - oncogene c - fos mRNA in cultured neonatal rat cardiomyocytes, which could be effectively decreased by buckwheat rutin. Our results demonstrated that buckwheat rutin exhibited inhibitory effect on AngII - induced hypertrophy in cultured neonatal rat cardiomyocytes via Ca2+ antagonism action thus block the CaN - dependent signal pathway.
PMCID: PMC4232801  PMID: 25587324
Rutin; Buckwheat; Angiotensin II; Cardiac hypertrophy; Calcineurin
6.  Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice 
Aging cell  2013;12(4):706-711.
SUMMARY
Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer’s disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5-lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid-mediated amyloid β (Ab) formation in vitro. In the current paper we investigated the role of this pathway in modulating the development of the corticosteroid-dependent AD-like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for one week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO−/−) mice and its effect on memory, amyloid-β and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Aβ levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF-13, which was specifically associated with an increase in the GSK3β activity. Additionally, dexamethasone-treated mice had a significant increase of the tau insoluble fraction, and reduction of the post-synaptic protein PDS-95. By contrast, these modifications were blunted in the 3xTg/5LO−/− mice. Our findings highlight the functional role that 5LO plays in stress-induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor.
doi:10.1111/acel.12096
PMCID: PMC3714329  PMID: 23634895
Alzheimer’s disease; transgenic mouse models; glucocorticoid; 5-lipoxygenase; amyloid; tau protein
7.  Fringe structures and tunable bandgap width of 2D boron nitride nanosheets 
Summary
We report studies of the surface fringe structures and tunable bandgap width of atomic-thin boron nitride nanosheets (BNNSs). BNNSs are synthesized by using digitally controlled pulse deposition techniques. The nanoscale morphologies of BNNSs are characterized by using scanning electron microscope (SEM), and transmission electron microscopy (TEM). In general, the BNNSs appear microscopically flat in the case of low temperature synthesis, whereas at high temperature conditions, it yields various curved structures. Experimental data reveal the evolutions of fringe structures. Functionalization of the BNNSs is completed with hydrogen plasma beam source in order to efficiently control bandgap width. The characterizations are based on Raman scattering spectroscopy, X-ray diffraction (XRD), and FTIR transmittance spectra. Red shifts of spectral lines are clearly visible after the functionalization, indicating the bandgap width of the BNNSs has been changed. However, simple treatments with hydrogen gas do not affect the bandgap width of the BNNSs.
doi:10.3762/bjnano.5.130
PMCID: PMC4142973  PMID: 25161852
boron nitride sheets; fringe patterns; functionalization; tunable bandgap width
8.  5-Lipoxygenase pharmacological blockade decreases tau phosphorylation in vivo: involvement of the cdk5 kinase 
Neurobiology of aging  2013;34(6):1549-1554.
The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer’s disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice. However, its contribution to tau pathology remains to be investigated. To this end we studied the effect of 5LO chronic pharmacologic inhibition on endogenous tau level and metabolism in the same mice. The phosphorylation of tau at S396 and S396/404 in the brains of mice receiving zileuton, a selective and specific 5LO inhibitor, was significantly reduced when compared with their controls, while there was no significant change of tau phosphorylation at S202/T205, T231/S235 and T181 epitopes. The 5LO-dependent reduction of tau phosphorylation resulted from a significant decrease in the level and activity of the cyclin-dependent kinase-5 but not other kinases. Our findings highlight the novel functional role that neuronal 5LO plays in modulating tau phosphorylation, and suggest that pharmacological inhibition of 5LO could provide a novel therapeutic opportunity also for AD-related tau pathology.
doi:10.1016/j.neurobiolaging.2012.12.009
PMCID: PMC3596429  PMID: 23332172
Alzheimer’s disease; transgenic mouse models; tau protein; beta amyloid; 5Lipoxygenase
9.  Stress Hormone Leads to Memory Deficits and Altered Tau Phosphorylation in a Model of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2012;31(1):10.3233/JAD-2012-120328.
Several studies have linked stress with Alzheimer’s disease (AD) vulnerability; however, the mechanism remains to be fully elucidated. In the current paper, we investigated the role of glucocortitcoids on the AD-like phenotype. We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, amyloid-β and tau levels, and metabolism. At the end of the treatment period, we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Aβ40 levels, but no alteration in the steady state levels of its precursor protein, AβPP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1, or γ-secretase complex). While total tau protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by decreases in glycogen synthase kinase-3β protein level and activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tau protein phosphorylation state.
doi:10.3233/JAD-2012-120328
PMCID: PMC3882896  PMID: 22531419
Alzheimer’s disease; transgenic animal model; stress; glucocorticoid
10.  Icariin Decreases the Expression of APP and BACE-1 and Reduces the β-amyloid Burden in an APP Transgenic Mouse Model of Alzheimer's Disease 
Objective: The purpose of this study was to investigate the effects and pharmacological mechanisms of icariin, which is the main component in the traditional Chinese herb Epimedium, on β-amyloid (Aβ) production in an amyloid precursor protein (APP) transgenic (Tg) mouse model of Alzheimer's disease (AD).
Methods: APPV717I Tg mice were randomly divided into a model group and icariin-treated (30 and 100 μmol/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition tests. Aβ contents were measured by enzyme-linked immunosorbent assays and immunohistochemistry. Amyloid plaques were detected by Congo red staining and Bielschowsky silver staining. The levels of expression of APP and β-site APP-cleaving enzyme 1 (BACE-1) were measured by western blotting and immunohistochemistry.
Results: Ten-month-old Tg mice showed obvious learning-memory impairments, and significant increases in Aβ contents, amyloid plaques, and APP and BACE-1 levels in the hippocampus. The intragastric administration of icariin to Tg mice for 6 months (from 4 to 10 months of age) improved the learning-memory abilities and significantly decreased the Aβ contents, amyloid plaques, and APP and BACE-1 levels in the hippocampus.
Conclusion: Icariin reduced the Aβ burden and amyloid plaque deposition in the hippocampus of APP transgenic mice by decreasing the APP and BACE-1 levels. These novel findings suggest that icariin may be a promising treatment in patients with AD.
doi:10.7150/ijbs.6232
PMCID: PMC3927130  PMID: 24550686
Icariin; Alzheimer's disease; APPV717I transgenic mice; β-amyloid; amyloid plaque; BACE-1; amyloid precursor protein
11.  5-Lipoxygenase gene transfer worsens memory, amyloid and tau brain pathologies in a mouse model of AD 
Annals of neurology  2012;72(3):442-454.
Objective
The 5-lipoxygenase (5LO) enzyme is up-regulated in Alzheimer’s disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.
Methods
To this end, we generated triple transgenic mice (3xTg-AD) over-expressing neuronal 5LO and investigated their phenotype.
Results
Compared with controls, 3xTg-AD mice over-expressing 5LO manifested an exacerbation of memory deficits, plaques and tangles pathologies. The elevation in Aβ was secondary to an up-regulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5-LO-dependent tau phosphorylation, which was independent of the effect on Aβ.
Interpretation
Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.
doi:10.1002/ana.23642
PMCID: PMC3464917  PMID: 23034916
12.  Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer’s Disease with Plaques and Tangles 
PLoS ONE  2013;8(8):e70991.
The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer’s disease (AD), and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3×Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.
doi:10.1371/journal.pone.0070991
PMCID: PMC3737232  PMID: 23951061
13.  Development and application of loop-mediated isothermal amplification assays on rapid detection of various types of staphylococci strains 
A loop-mediated isothermal amplification (LAMP) method for rapid detection of various Staphylococcus strains and associated antibiotic resistance determinant had been developed and evaluated in this study. Six primers, including outer primers, inner primers and loop primers, were specially designed for recognizing eight distinct sequences on three targets: 16SrRNA, femA and mecA.. Forty-one reference strains, including various species of gram-negative and -positive isolates, were included in this study to evaluate and optimize LAMP assays. The optimal reaction condition was found to be 65 °C for 45 min, with detection limits at 100 fg DNA/tube and 10 CFU/reaction for 16S rRNA, 100 fg DNA/tube and 10 CFU/reaction for femA, 1 pg DNA/tube and 100 CFU/reaction for mecA, respectively. Application of LAMP assays were performed on 118 various types of Staphylococcus isolates, the detection rate of LAMP assays for the 16SrRNA, femA and mecA was 100% (118/118), 98.5% (64/65) and 94.3% (66/70), and the negative predictive value (NPV) was 100%, 98.1% and 92.3% respectively; with a 100% positive predictive value (PPV) for all three targets. In conclusion, LAMP assays were demonstrated to be useful and powerful tools for rapid detection of various Staphylococcus strains, and undoubtedly, the rapidness, technical simplicity, and cost-effectiveness of LAMP assays will demonstrate broad application for bacteriological detection of food-borne Methicillin-resistant Staphylococcus (MRS) isolates.
doi:10.1016/j.foodres.2011.04.042
PMCID: PMC3390935  PMID: 22778501
Loop-mediated isothermal amplification; Rapid detection; Food-borne Staphylococci; MRSA; MRCNS
14.  Transcriptional regulation of Beta secretase-1 by 12-15Lipoxygenase results in enhanced amyloidogenesis and cognitive impairments 
Annals of Neurology  2012;71(1):57-67.
Objective
The 12-15Lipoxygenase (12-15LO) is an enzyme widely distributed in the central nervous system and it has been involved in the neurobiology of Alzheimer’s disease (AD). However, the mechanism involved remains elusive.
Methods
We investigated the molecular mechanism by which 12-15LO regulates Amyloid β/APP metabolism in vivo and in vitro by genetic and pharmacologic approaches.
Results
Here we show that over-expression of 12-15LO leads to increased levels of BACE1 mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice.
In vitro and in vivo studies demonstrate that 12-15LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12-15LO-overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15LO-deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant negative mutant blocks the 12-15LO-dependent elevation of Aβ and BACE1 levels.
Interpretation
Our findings demonstrate a novel pathway by which 12-15LO increases the amyloidogenic processing of APP through a Sp1-mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy.
doi:10.1002/ana.22625
PMCID: PMC3270901  PMID: 22275252
15.  Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer’s disease mouse model 
Background
The 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein, called 5-lipoxygenase activating protein. While previous works have shown that 5-lipoxygenase is involved in the pathogenesis of Alzheimer’s disease, no data are available on the role that 5-lipoxygenase activating protein plays in Alzheimer’s disease.
Methods
In the present paper, we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of Tg2576 mice.
Results
Amyloid β peptide (Aβ) deposition in the brains of mice receiving MK-591, a selective and specific 5-lipoxygenase activating protein inhibitor, was significantly reduced when compared with controls. This reduction was associated with a similar decrease in brain Aβ peptides levels. MK-591 treatment did not induce any change in the steady-state levels of amyloid-β precursor protein, β-site amyloid precursor protein cleaving enzyme 1 or disintegrin and metalloproteinase domain-containing protein 10. By contrast, it resulted in a significant reduction of the γ-secretase complex, at the protein and message level. Furthermore, in vitro studies confirmed that MK-591 prevents Aβ formation by modulating γ-secretase complex levels without affecting Notch signaling.
Conclusions
These data establish a novel functional role for 5-lipoxygenase activating protein in the pathogenesis of Alzheimer’s disease-like amyloidosis, and suggest that its pharmacological inhibition could provide a novel therapeutic opportunity for Alzheimer’s disease.
doi:10.1186/1742-2094-9-127
PMCID: PMC3425138  PMID: 22697885
Alzheimer’s disease; Amyloid β; Amyloid beta precursor protein; Animal model; 5-lipoxygenase activating protein
16.  Conducting composite materials from the biopolymer kappa-carrageenan and carbon nanotubes 
Summary
Conducting composite films containing carbon nanotubes (CNTs) were prepared by using the biopolymer kappa-carrageenan (KC) as a dispersant. Rheological studies indicated that 0.5% w/v was the appropriate KC concentration for dispersing CNTs. Our results showed that multiwalled nanotubes (MWNTs) required less sonic energy than single-walled nanotubes (SWNTs) for the dispersion process to be complete. Films prepared by vacuum filtration exhibited higher conductivity and improved mechanical characteristics compared to those prepared by evaporative casting. All composite films displayed sensitivity to water vapour, but MWNT films were more sensitive than SWNT films.
doi:10.3762/bjnano.3.48
PMCID: PMC3388366  PMID: 23016146
biopolymers; carbon nanotubes; carrageenan; composite materials; conductivity; mechanical; rheology
17.  Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice 
Background
The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice.
Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology.
Results
Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2.
Conclusions
These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.
doi:10.1186/1750-1326-7-1
PMCID: PMC3277480  PMID: 22222029
Alzheimer's disease; animal model; amyloid beta; 5-Lipoxygenase
18.  5-Lipoxygenase as an endogenous modulator of amyloid beta formation in vivo 
Annals of neurology  2010;69(1):34-46.
Objective
The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is up-regulated in Alzheimer's disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive.
Methods
We evaluated the molecular mechanism by which 5-LO regulates Amyloid β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches.
Results
Here we show that 5-LO regulates the formation of Aβ by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the γ-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of Aβ formation and the increase of γ-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Aβ, CREB and γ-secretase levels.
Interpretation
These data establish a novel functional role for 5-LO in regulating endogenous formation of Aβ levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer's disease.
doi:10.1002/ana.22234
PMCID: PMC3051361  PMID: 21280074
19.  The Effects of Total Flavonoids from Buckwheat Flowers and Leaves on Renal Damage and PTP1B Expression in Type 2 Diabetic Rats 
Clinical data showed consumption of buckwheat played a very positive role in the relief of diabetes and its complications. The purpose of this study was to explore the effects and mechanisms of the overall flavonoids from buckwheat flowers and leaves (TFBFL) on renal damage in type 2 diabetes mellitus (T2DM) rats. Seventy male Wistar rats were selected. Ten rats were randomly allocated into a normal group and the other sixty were intragastrically injected with a lipid emulsion and small doses of alloxan to induce the T2DM model. T2DM inducement was judged by the fasting blood glucose (FBG) and oral glucose tolerance test (OGTT). Those whose FBG was ≥ 16.7 mmol/L and less tolerant to glucose were considered as being T2DM rats. These rats were then randomly divided into a groups termed: model (purified water, 5 mL.kg-1 . d-1), BNPL (positive control) (Benazepril, 4 mg.kg-1 . d-1), L-TFBFL (TFBFL 100 mg.kg-1 . d-1), M-TFBFL (TBFL 200 mg.kg-1 . d-1) and H-TFBFL (TFBFL 400 mg.kg-1 . d-1). Each group then received medication for a period of 4 weeks. The normal rats were treated with purified water in a synchronous manner. Subsequently, FBG, plasma insulin (INS), OGTT, 24 h urinary protein output, blood and urinary creatinine content were assayed. Then the insulin sensitive index (ISI), bilateral kidney index, and creatinine clearance rate (Ccr) were calculated. Renal morphological changes and expression of protein tyrosine phosphatase 1B (PTP1B) in the kidneys were observed. TFBFL lowered FBG, improved insulin resistance, caused Ccr, and renal morphological changes, down-regulated the expression of PTP1B in T2DM rats and showed dose-dependence. TFBFL had a significant protective effect on renal damage in T2DM rats. This effect may be due to lowering blood glucose and diminishing renal damage by inhibiting PTP1B expression.
PMCID: PMC3813022  PMID: 24250383
Buckwheat; Flavonoids; Type 2 diabetes mellitus; Renal damage; PTP1B
20.  Involvement of 5-Lipoxygenase in the Corticosteroid-Dependent Amyloid Beta Formation: In Vitro and In Vivo Evidence 
PLoS ONE  2011;6(1):e15163.
Background
Numerous studies show that high circulating level of glucocorticosteroids is a biochemical characteristic of Alzheimer's disease (AD). These stress hormones can increase the amount of AD-like pathology in animal models of the disease. Since they also up-regulate the 5-Lipoxygenase (5-LO), an enzyme which modulates amyloid beta (Aβ) formation, in the present paper we tested the hypothesis that this enzymatic pathway is involved in the glucocorticoid-induced pro-amyloidotic effect.
Methodology/Principal Findings
Incubation of neuronal cells with dexamethasone resulted in a significant increase in 5-LO activity and Aβ formation. By contrast, pharmacological inhibition of 5-LO prevented the dexamethasone-dependent increase in Aβ levels. Mouse embryonic fibroblasts responded with a significant increase in Aβ formation after dexamethasone challenge. However, this effect was abolished when dexamethasone was incubated with fibroblasts genetically deficient for 5-LO. No difference in the glucocorticoid receptor levels was observed between the two groups. Finally, treatment of wild type mice with dexamethasone resulted in a significant increase in endogenous brain Aβ levels, which was prevented in mice genetically lacking 5-LO.
Conclusions
These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology.
doi:10.1371/journal.pone.0015163
PMCID: PMC3017076  PMID: 21253592
21.  The 5-Lipoxygenase as a Common Pathway for Pathological Brain and Vascular Aging 
Epidemiological studies indicate age as a strong risk factor for developing cardiovascular and neurodegenerative diseases. During the aging process, changes in the expression of particular genes can influence the susceptibility to these diseases. 5-Lipoxygenase (5-LO) by oxidizing fatty acids forms leukotrienes, potent mediators of oxidative and inflammatory reactions, two key pathogenic events in both clinical settings. This enzyme is widely distributed in the cardiovascular as well as in the central nervous system, where its expression levels increase with age, suggesting that it may be involved in their diseases of aging. The central theme of this article is that during aging, 5-LO acts as biologic link between different stressors and the development of cardiovascular and neurodegenerative diseases. We hypothesize that the age-dependent upregulation of 5-LO represents a “priming” factor in the vasculature as well as in the brain, where a subsequent exposure to triggering stimuli (i.e., infections) leads to an abnormal chronic inflammatory reaction, and ultimately results in increased organ vulnerability and functional deficits.
doi:10.1155/2009/174657
PMCID: PMC2775696  PMID: 19936103

Results 1-21 (21)