As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their... more
As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their contribution to cognitive decline remain one of the most fundamental and unresolved questions in the AD field. Likewise, elucidating the initial triggers of disease pathology, as well as the impact of various factors such as stress and inflammation on disease progression, are equally important to fully understand this devastating disorder. Here we discuss recent studies that have illuminated the importance of key facilitators of disease progression using the 3xTg-AD and CaM/Tet-DTA mouse models, and suggest viable targets for ameliorating both molecular pathology and cognitive decline.
Research Interests:
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ... more
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented g...
Research Interests:
Research Interests:
Research Interests: Chemistry, Cell Biology, Lipopolysaccharide, Dexamethasone, Protein Kinases, and 15 moreFemale, Animals, Male, Kinase inhibitor, Transcription Factor, Time Dependent, Isoenzymes, Muscle contraction, Protein Kinase, Rabbits, Aorta, Tyrosine Kinase, Protein Kinase C, Medical and Health Sciences, and In Vitro Techniques
Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated... more
Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.
Research Interests:
Research Interests: Psychology, Chemistry, Neuropharmacology, Medicine, Hippocampus, and 15 moreMice, Animals, Male, Phosphorylation, Neurons, Calpain, Alzheimer Disease, Molecular Targeted Therapy, Neurosciences, Benzamides, Cysteine Proteinase Inhibitors, Tau proteins, Stress Physiological, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests:
Research Interests: Animal Behavior, Medicine, Dopamine, Learning and Memory, Brain, and 15 moreAnimals, Male, Central Nervous System, Enzyme, Clinical Sciences, Experimental, Cognitive Function, Experimental Neurology, Intranasal Administration, Epidemiologic Studies, Maze Learning, Early Diagnosis, Intranasal, Morris water maze, and Motor activity
Research Interests: Biology, Membrane Proteins, Medicine, Mice, Animals, and 15 moreMale, Skin, Phosphorylation, Anti-inflammatory agents, Mitogen Activated Protein Kinase, Inflammatory disease, Topical Drug Administration, Time Factors, Western blot, Protein Kinase, Phorbol ester, Oleanolic acid, Enzyme Induction, Protein Kinase C, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, British, Medicine, Signal Transduction, Smooth muscle, and 15 moreNitric oxide, Female, Animals, Male, Epithelium, Nitric Oxide Synthase, Trachea, Guinea Pig, Muscle Relaxation, Tyrosine Kinase, Bradykinin, Protein tyrosine kinases, Guinea pigs, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests:
Research Interests: Genetics, Enzyme Inhibitors, Drug development, Signal Transduction, Antibodies, and 15 moreHippocampus, Mice, Animals, Cognitive impairment, Analysis of Variance, Cognitive Function, Protein Kinase, Cognitive Decline, Maze Learning, Intracellular Signaling, Cognition disorders, Psychology and Cognitive Sciences, Signaling pathway, Protein Kinase C, and Medical and Health Sciences
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of... more
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of gabapentin, a drug used clinically for the management of neuropathic pain. Similar to gabapentin, diacerhein was able to significantly reverse the mechanical allodynia induced by carrageenan. A significant inhibition of carrageenan-induced nociception was also observed when diacerhein was administered by the intrathecal but not by the intraplantar route. The treatment with diacerhein or with gabapentin also inhibited the mechanical allodynia induced by complete Freund's adjuvant (CFA) or after the partial ligation of the sciatic nerve (PLSN). In the same range of doses, diacerhein or gabapentin did not affect the locomotor activity, motor coordination, or body temperature of the animals. The present results indicate that diacerhein produces marked antiallodynic effects in carrageenan and CFA nociception models and also inhibits the neuropathic pain after PLSN, with an efficacy similar to that observed for gabapentin. Diacerhein may be a potentially interesting tool for the management of inflammatory and neuropathic pain.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all... more
Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer's disease. Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed. High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75% lower-dose results in sustained elimination of ~30 of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg...
Research Interests:
Research Interests:
Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism,... more
Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ₁₋₄₀-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our...
Research Interests:
As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their... more
As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their contribution to cognitive decline remain one of the most fundamental and unresolved questions in the AD field. Likewise, elucidating the initial triggers of disease pathology, as well as the impact of various factors such as stress and inflammation on disease progression, are equally important to fully understand this devastating disorder. Here we discuss recent studies that have illuminated the importance of key facilitators of disease progression using the 3xTg-AD and CaM/Tet-DTA mouse models, and suggest viable targets for ameliorating both molecular pathology and cognitive decline.
Research Interests:
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ... more
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented g...
Research Interests:
Research Interests:
Research Interests: Chemistry, Cell Biology, Lipopolysaccharide, Dexamethasone, Protein Kinases, and 15 moreFemale, Animals, Male, Kinase inhibitor, Transcription Factor, Time Dependent, Isoenzymes, Muscle contraction, Protein Kinase, Rabbits, Aorta, Tyrosine Kinase, Protein Kinase C, Medical and Health Sciences, and In Vitro Techniques
Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated... more
Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.
Research Interests:
Research Interests: Psychology, Chemistry, Neuropharmacology, Medicine, Hippocampus, and 15 moreMice, Animals, Male, Phosphorylation, Neurons, Calpain, Alzheimer Disease, Molecular Targeted Therapy, Neurosciences, Benzamides, Cysteine Proteinase Inhibitors, Tau proteins, Stress Physiological, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests:
Research Interests: Animal Behavior, Medicine, Dopamine, Learning and Memory, Brain, and 15 moreAnimals, Male, Central Nervous System, Enzyme, Clinical Sciences, Experimental, Cognitive Function, Experimental Neurology, Intranasal Administration, Epidemiologic Studies, Maze Learning, Early Diagnosis, Intranasal, Morris water maze, and Motor activity
Research Interests: Biology, Membrane Proteins, Medicine, Mice, Animals, and 15 moreMale, Skin, Phosphorylation, Anti-inflammatory agents, Mitogen Activated Protein Kinase, Inflammatory disease, Topical Drug Administration, Time Factors, Western blot, Protein Kinase, Phorbol ester, Oleanolic acid, Enzyme Induction, Protein Kinase C, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, British, Medicine, Signal Transduction, Smooth muscle, and 15 moreNitric oxide, Female, Animals, Male, Epithelium, Nitric Oxide Synthase, Trachea, Guinea Pig, Muscle Relaxation, Tyrosine Kinase, Bradykinin, Protein tyrosine kinases, Guinea pigs, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests:
Research Interests: Genetics, Enzyme Inhibitors, Drug development, Signal Transduction, Antibodies, and 15 moreHippocampus, Mice, Animals, Cognitive impairment, Analysis of Variance, Cognitive Function, Protein Kinase, Cognitive Decline, Maze Learning, Intracellular Signaling, Cognition disorders, Psychology and Cognitive Sciences, Signaling pathway, Protein Kinase C, and Medical and Health Sciences
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of... more
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of gabapentin, a drug used clinically for the management of neuropathic pain. Similar to gabapentin, diacerhein was able to significantly reverse the mechanical allodynia induced by carrageenan. A significant inhibition of carrageenan-induced nociception was also observed when diacerhein was administered by the intrathecal but not by the intraplantar route. The treatment with diacerhein or with gabapentin also inhibited the mechanical allodynia induced by complete Freund's adjuvant (CFA) or after the partial ligation of the sciatic nerve (PLSN). In the same range of doses, diacerhein or gabapentin did not affect the locomotor activity, motor coordination, or body temperature of the animals. The present results indicate that diacerhein produces marked antiallodynic effects in carrageenan and CFA nociception models and also inhibits the neuropathic pain after PLSN, with an efficacy similar to that observed for gabapentin. Diacerhein may be a potentially interesting tool for the management of inflammatory and neuropathic pain.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals. Stress is an important etiological factor that contributes to the progression of aging and Alzheimer’s disease (AD).... more
Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals. Stress is an important etiological factor that contributes to the progression of aging and Alzheimer’s disease (AD). Stress and the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating glucocorticoid (GC) hormone levels, are intimately related. Excess GC secretion has been documented as an early feature of AD, implicated in the pathogenesis (neuronal atrophy, dysfunction, and memory impairments). We previously showed that excessive circulating GC upregulate both Ab and tau pathologies in the 3xTg-AD mouse model. Methods: The aim of the present study was to analyze the effect of the glucocorticoid antagonist RU-486 (mifepristone: 17b-hydroxy11a-(4-dimethylaminophenyl)-17a-(1-propynyl)-estra-4, 9dien-3-one; Innovative Research of America, Sarasota, FL) in the 3xTg-AD mice at an age where extensive hippocampal damage leads to upregulated circulating corticosterone levels. Mifepristone pellets (15 mg pellets and 60-day release at continuous flow of 10mg/h) were implanted intrascapularly in the 3xTg-AD at 12 months of age. Results: Mifepristone treatment reduced plasma corticosterone levels and brain GC receptor levels, compared to vehicle-implanted animals. Notably, treated mice showed an improvement in several cognitive tests (novel context, place, and object recognition; Morris water mice). These cognitive improvements were associated with a drastic reduction in both soluble and insoluble Ab levels as well as robust reductions in steady state levels of tau, including reduced somatodendritic accumulation within hippocampal neurons. Conclusions: Our findings demonstrate that anti-glucocorticoid strategies could be effective for the treatment of AD, and crucially show robust disease modifying effects in addition to preventing the effects of elevated circulating glucocorticoids.