USF Health Byrd Alzheimers Institute

Tampa, FL, United States

USF Health Byrd Alzheimers Institute

Tampa, FL, United States
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PubMed | University of South Florida, University of California at Davis and USF Health Byrd Alzheimers Institute
Type: | Journal: Neuropharmacology | Year: 2016

Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABA


PubMed | Laboratory of Molecular Biology, USF Tampa, USF Health Byrd Alzheimers Institute and Current Inc.
Type: Journal Article | Journal: American journal of neurodegenerative disease | Year: 2016

Transcription factors are involved to varying extents in the health and survival of neurons in the brain and a better understanding of their roles with respect to the pathogenesis of Alzheimers disease (AD) could lead to the development of additional treatment strategies. Sp1 is a transcription factor that responds to inflammatory signals occurring in the AD brain. It is known to regulate genes with demonstrated importance in AD, and we have previously found it upregulated in the AD brain and in brains of transgenic AD model mice. To better understand the role of Sp1 in AD, we tested whether we could affect memory function (measured with a battery of behavioral tests discriminating different aspects of cognitive function) in a transgenic model of AD by pharmaceutical modulation of Sp1. We found that inhibition of Sp1 function in transgenic AD model mice increased memory deficits, while there were no changes in sensorimotor or anxiety tests. A42 and A40 peptide levels were significantly higher in the treated mice, indicating that Sp1 elevation in AD could be a functionally protective response. Circulating levels of CXCL1 (KC) decreased following treatment with mithramycin, while a battery of other cytokines, including IL-1, IL-6, INF- and MCP-1, were unchanged. Gene expression levels for several genes important to neuronal health were determined by qRT-PCR, and none of these appeared to change at the transcriptional level.


PubMed | University of Kentucky, University of Washington, The Dead Sea and Arava Science Center, University of Rochester and 10 more.
Type: Journal Article | Journal: Journal of neurochemistry | Year: 2016

Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimers disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimers disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimers disease are further contributions to this article.


Benbadis S.R.,University of South Florida | Sanchez-Ramos J.,University of South Florida | Bozorg A.,University of South Florida | Giarratano M.,University of South Florida | And 6 more authors.
Expert Review of Neurotherapeutics | Year: 2014

Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ9-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS 'depressants' and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will likely expand. © Informa UK, Ltd.


Judge M.,USF Health Byrd Alzheimers Institute | Hornbeck L.,University of South Florida | Hornbeck L.,USF Health Byrd Alzheimers Institute | Potter H.,University of South Florida | And 3 more authors.
Molecular Neurodegeneration | Year: 2011

Background: Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. Results: Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate A and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition. Conclusions: The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of APP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into A and the C-terminal fragment suggest that these proteins may have a normal function during mitosis. © 2011 Judge et al; licensee BioMed Central Ltd.


Woods N.K.,USF Health Byrd Alzheimers Institute | Woods N.K.,University of South Florida | Padmanabhan J.,USF Health Byrd Alzheimers Institute | Padmanabhan J.,University of South Florida
Journal of Biological Chemistry | Year: 2013

Background: Amyloid precursor protein (APP) and ADAM10, main α-secretase involved in generation of secreted APP (sAPPα), are overexpressed in pancreatic cancer. Results: Inhibition of APP processing by ADAM10 prevents anchorage independent growth and survival of cancer cells. Conclusion: Inhibition of sAPPα generation enhances chemotherapeutic potential of gemcitabine. Significance: Supplementing established pancreatic cancer therapy regimen with sAPPα inhibition will significantly improve the efficacy of treatment. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Niu Y.,University of South Florida | Padhee S.,University of South Florida | Wu H.,University of South Florida | Bai G.,University of South Florida | And 5 more authors.
Chemical Communications | Year: 2011

We report the identification of a new class of antimicrobial peptidomimetics-γ-AApeptides with potent and broad-spectrum activity, including clinically-relevant strains that are unresponsive to most antibiotics. They are also not prone to select for drug-resistance. © The Royal Society of Chemistry 2011.


Padhee S.,University of South Florida | Hu Y.,University of South Florida | Niu Y.,University of South Florida | Bai G.,University of South Florida | And 7 more authors.
Chemical Communications | Year: 2011

We report a new class of peptide mimetics, α-AApeptides, that display broad-spectrum activity against both Gram-negative and Gram-positive bacteria and fungi. With non-hemolytic activity, resistance to protease hydrolysis, and easy sequence programmability, α-AApeptides may emerge as a novel class of antibiotics. © The Royal Society of Chemistry 2011.


Brownlow M.L.,University of South Florida | Brownlow M.L.,USF Health Byrd Alzheimers Institute | Benner L.,USF Health Byrd Alzheimers Institute | D'Agostino D.,University of South Florida | And 4 more authors.
PLoS ONE | Year: 2013

Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition. © 2013 Brownlow et al.


Palavicini J.P.,Torrey Pines Institute for Molecular Studies | Wang H.,Torrey Pines Institute for Molecular Studies | Bianchi E.,Institute Pasteur Paris | Xu S.,Florida Institute of Technology | And 3 more authors.
Cell Death and Disease | Year: 2013

We previously demonstrated that overexpression of RanBP9 led to enhanced Aβ generation in a variety of cell lines and primary neuronal cultures, and subsequently, we confirmed increased amyloid plaque burden in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin protein levels when RanBP9 is overexpressed. At 12 months of age, we found spinophilin levels reduced by 70% (P<0.001) in the cortex of APΔE9/RanBP9 mice compared with that in wild-type (WT) controls. In the hippocampus, the spinophilin levels were reduced by 45% (P<0.01) in the APΔE9/RanBP9 mice. Spinophilin immunoreactivity was also reduced by 22% (P<0.01) and 12% (P<0.05) in the cortex of APΔE9/RanBP9 and APΔE9 mice, respectively. In the hippocampus, the reductions were 27% (P<0.001) and 14% (P<0.001) in the APΔE9/RanBP9 and APΔE9 mice, respectively. However, in the cerebellum, spinophilin levels were not altered in either APΔE9 or APΔE9/RanBP9 mice. Additionally, synaptosomal functional integrity was reduced under basal conditions by 39% (P<0.001) in the APΔE9/RanBP9 mice and ∼23% (P<0.001) in the APΔE9 mice compared with that in WT controls. Under ATP-and KCl-stimulated conditions, we observed higher mitochondrial activity in the WT and APΔE9 mice, but lower in the APΔE9/RanBP9 mice. Significantly, we confirmed the inverse relationship between RanBP9-N60 and spinophilin in the synaptosomes of Alzheimer's brains. More importantly, both APΔE9 and APΔE9/RanBP9 mice showed impaired learning and memory skills compared to WT controls. These data suggest that RanBP9 might play a crucial role in the loss of spines and synapses in AD. © 2013 Macmillan Publishers Limited All rights reserved. © 2013 Macmillan Publishers Limited All rights reserved.

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