Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model

Beta-amyloid (Aβ) oligomers contribute to the pathophysiology of Alzheimer disease (AD), and metabotropic glutamate receptor 5 (mGluR5) has been shown to act as a receptor for both Aβ oligomers and cellular prion proteins. Furthermore, the genetic deletion of mGluR5 in an APPswe/PS1δE9 mouse model of AD improves cognitive function and reduces Aβ plaques and Aβ oligomer concentrations. Here, we show that chronic administration of the orally bioavailable mGluR5-selective negative allosteric modulator CTEP, which is similar in structure, potency, and selectivity to Basimglurant (RO4917523), which is currently in phase II clinical development for major depressive disorder and fragile X syndrome, reverses cognitive decline in APPswe/PS1δE9 mice and reduces Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1δE9 and 3xTg-AD male mice. These findings suggest that CTEP or its analogue Basimglutant might potentially be an effective therapeutic for the treatment of AD patients

What's wrong with the murals at the Mogao Grottoes : a near-infrared hyperspectral imaging method

Although a significant amount of work has been performed to preserve the ancient murals in the Mogao Grottoes by Dunhuang Cultural Research, non-contact methods need to be developed to effectively evaluate the degree of flaking of the murals. In this study, we propose to evaluate the flaking by automatically analyzing hyperspectral images that were scanned at the site. Murals with various degrees of flaking were scanned in the 126th cave using a near-infrared (NIR) hyperspectral camera with a spectral range of approximately 900 to 1700 nm. The regions of interest (ROIs) of the murals were manually labeled and grouped into four levels: normal, slight, moderate, and severe. The average spectral data from each ROI and its group label were used to train our classification model. To predict the degree of flaking, we adopted four algorithms: deep belief networks (DBNs), partial least squares regression (PLSR), principal component analysis with a support vector machine (PCA + SVM) and principal component analysis with an artificial neural network (PCA + ANN). The experimental results show the effectiveness of our method. In particular, better results are obtained using DBNs when the training data contain a significant amount of striping noise

Neuroprotective effects of direct activation and transactivation of PDGFβ receptors

Platelet-derived growth factor (PDGF) receptors are expressed throughout the body, including the central nervous system (CNS). Although the physiological role of PDGF receptors in the developed CNS is not fully characterized, PDGF signaling appears to provide neuroprotective effects against several neuronal insults. One of the best-characterized neuroprotective effects of PDGF type-β receptors is against human immunodeficiency virus (HIV) protein-induced neurotoxicity, with potential physiological relevance to HAD. PDGFβ receptors are also neuroprotective against glutamate excitotoxicity, which is associated with both stroke and neurodegenerative diseases, including Alzheimer’s disease. The neuroprotective effects of PDGFβ receptors occur both via direct activation by ligand (PDGF-BB), as well as by PDGFβ receptors activated downstream of G protein-coupled receptor signaling. In addition to the involvement of PDGF signaling in various pathologies and potential therapies, there is also an emerging body of evidence that PDGF may serve as a biomarker for neurological or psychiatric diseases

Analysis of Particle Dispersion in Turbulent Mixed Convection of CuO-water Nanofluid

In the present paper, turbulent convection of CuO-Water Nanofluid in a vertical channel is investigated numerically. In order to simulate the flow, the fluid is considered as a continuous phase while the discrete nanoparticles are dispersed through it. The dispersion of CuO nanoparticles in different flow conditions are studied in order to find the effective mechanisms of particles dispersion in the channel. The results show that in the fully developed turbulent convection flow, thermophoresis is more dominant than Brownian motion of nanoparticles and therefore the nanoparticles aggregation are more in the central areas of the channel. While in entrance region, where the boundary layer is not fully formed, the particles dispersion are more uniform. Also, an increase in the nanoparticles concentration will increase the turbulent velocity fluctuations in regions near the wall and this two-sided effect will cause improvement in turbulent flow thermal transmitance than the laminar flow

Reactive oxygen species are required for 5-HT-induced transactivation of neuronal platelet-derived growth factor and TrkB receptors, but not for ERK1/2 activation.

High concentrations of reactive oxygen species (ROS) induce cellular damage, however at lower concentrations ROS act as intracellular second messengers. In this study, we demonstrate that serotonin (5-HT) transactivates the platelet-derived growth factor (PDGF) type β receptor as well as the TrkB receptor in neuronal cultures and SH-SY5Y cells, and that the transactivation of both receptors is ROS-dependent. Exogenous application of H₂O₂ induced the phosphorylation of these receptors in a dose-dependent fashion, similar to that observed with 5-HT. However the same concentrations of H₂O₂ failed to increase ERK1/2 phosphorylation. Yet, the NADPH oxidase inhibitors diphenyleneiodonium chloride and apocynin blocked both 5-HT-induced PDGFβ receptor phosphorylation and ERK1/2 phosphorylation. The increases in PDGFβ receptor and ERK1/2 phosphorylation were also dependent on protein kinase C activity, likely acting upstream of NADPH oxidase. Additionally, although the ROS scavenger N-acetyl-l-cysteine abrogated 5-HT-induced PDGFβ and TrkB receptor transactivation, it was unable to prevent 5-HT-induced ERK1/2 phosphorylation. Thus, the divergence point for 5-HT-induced receptor tyrosine kinase (RTK) transactivation and ERK1/2 phosphorylation occurs at the level of NADPH oxidase in this system. The ability of 5-HT to induce the production of ROS resulting in transactivation of both PDGFβ and TrkB receptors may suggest that instead of a single GPCR to single RTK pathway, a less selective, more global RTK response to GPCR activation is occurring

H₂O₂ increases PDGFβ receptor phosphorylation in SH-SY5Y cells and primary neuron cultures.

<p>(A) SH-SY5Y cells were treated with vehicle (VEH) or 0.01 to 100 µM H₂O₂ for 5 min. Following drug treatments, cell lysates were evaluated by Western blot analysis as described in Materials and Methods. Data were normalized to total PDGFRβ protein expression and are expressed as the fold change (average ± S.E.M.) in phospho-1021 immunoreactivity compared to vehicle-treated cells. Representative blots for phospho-PDGFRβ 1021 (pY1021) and PDGFRβ at 180 kDa are shown. (B) Primary mouse cortical neuron cultures were treated with 0.1 µM H₂O₂ for 5 min. Lysates were evaluated for phospho-Y1021 as described in “A”. (C) SH-SY5Y cell cultures were pretreated with vehicle or 1000 µM of the ROS scavenger <i>N</i>-acetyl-l-cysteine (NAC) for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min. (Data are representative of 4-6 independent experiments. * = p < 0.05 compared to vehicle-treated cells; # = p < 0.05 compared to 5-HT-treated cells, one-way ANOVA, Tukey post-test, or Student’s t-test).</p

5-HT-induced PDGFβ receptor transactivation requires PKC and NADPH oxidase.

<p>(A) SH-SY5Y cell cultures were pretreated with vehicle or 0.1, 1 or 10 µM of the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min. Following drug treatments, cell lysates were evaluated by immunoblot analysis as described in Materials and Methods. Data were normalized to total PDGFRβ protein expression and are expressed as the fold change (average ± S.E.M.) in phospho-1021 immunoreactivity compared to vehicle-treated cells. Representative blots for phospho-PDGFRβ 1021 (pY1021) and PDGFRβ at 180 kDa are shown. (B) Cell cultures were pretreated with vehicle or 1, 10 or 100 µM of the NADPH oxidase inhibitor apocynin for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min, and results were analyzed for phospho-Y1021 as described in “A”. (C) Cultures were pretreated with vehicle or 0.1 µM of the PKC inhibitor Go 6983 for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min, and results were analyzed for phospho-Y1021 as described in “A”. (Data are representative of 3-5 independent experiments. * = p < 0.05 compared to vehicle-treated cells; # = p < 0.05 compared to 5-HT-treated cells, one-way ANOVA, Tukey post-test).</p

5-HT can transactivate TrkB receptors via ROS.

<p>(A) SH-SY5Y cells were treated with vehicle (VEH) or 0.01 to 10 µM H₂O₂ for 5 min. Following drug treatments, cell lysates were evaluated by Western blot analysis as described in Materials and Methods. Data were normalized to total TrkB protein expression and are expressed as the fold change (average ± S.E.M.) in TrkB phospho-816 immunoreactivity compared to vehicle-treated cells. Representative blots for phospho-TrkB Y816 (pY816) and TrkB at 145 kDa are shown. (B) Cell cultures were incubated with 0.1 µM 5-HT for 0, 1, 2, 5, 10, or 15 min, and fold change in TrkB Y816 phosphorylation was measured with respect to vehicle. (C) Cultures were pretreated with vehicle or 1000 µM of the ROS scavenger <i>N</i>-acetyl-l-cysteine (NAC) for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min. Normalized data was analyzed for phospho-TrkB Y816. (D) Cells were incubated overnight with 0.01 or 0.1 µg/mL pertussis toxin (Ptx) followed by 5 min treatment with 0.1 µM 5-HT. (E) Cell cultures were pretreated with vehicle or 1 or 10 µM of the PDGF receptor kinase inhibitor AG 1296 for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min. Western blots were evaluated for changes in phospho-TrkB Y816. (Data are representative of 5-6 independent experiments. * = p < 0.05 compared to vehicle-treated cells; # = p < 0.05 compared to 5-HT-treated cells, one-way ANOVA, Tukey post-test).</p

5-HT induced ERK1/2 phosphorylation diverges from the transactivation pathway at or after NADPH oxidase.

<p>(A) SH-SY5Y cells were treated with 0.01 to 100 µM H₂O₂ for 5 min. Following drug treatments, cell lysates were evaluated by Western blot analysis as described in Materials and Methods. Data were normalized to total ERK1/2 protein expression and are expressed as the fold change (average ± S.E.M.) in phospho-ERK immunoreactivity compared to vehicle-treated cells. (B) SH-SY5Y cell cultures were pretreated with vehicle or 10, 100 or 1000 µM of the ROS scavenger <i>N</i>-acetyl-l-cysteine (NAC) for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min and lysates were evaluated as in “A”. Cell cultures were also pretreated with vehicle or the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) (C) or apocynin (D) for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min, and results were analyzed for phospho-ERK1/2 as described in “A”. (E) Cultures were pretreated with vehicle or 0.1 µM of the PKC inhibitor Go 6983 for 45 min followed by treatment with vehicle or 100 nM 5-HT for 5 min, and results were analyzed for phospho-ERK1/2 as described above. Representative blots of phospho-ERK1/2 and total ERK1/2 at 42 and 44 kDa are shown. (Data are representative of 4-8 independent experiments. * = p < 0.05 compared to vehicle-treated cells; # = p < 0.05 compared to 5-HT-treated cells, one-way ANOVA, Tukey post-test).</p

H₂O₂ concentrations sufficient for inducing PDGFβ receptor phosphorylation do not result in cell death.

<p>SH-SY5Y cells were treated with 0, 0.1, 1, 10, 100, or 1000 µM H₂O₂ for (A) 30 min, or (B) overnight. Following treatment with MTT reagents and lysis, cell viability was measured and compared to control (VEH) values. (Data are representative of 4 independent experiments. * = p < 0.05 compared to vehicle-treated cells, one-way ANOVA, Tukey post-test).</p