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Mouse modell for alzheimers disease

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https://www.readbyqxmd.com/read/27906174/therapeutic-advantage-of-pro-electrophilic-drugs-to-activate-the-nrf2-are-pathway-in-alzheimer-s-disease-models
#1
Stuart A Lipton, Tayebeh Rezaie, Anthony Nutter, Kevin M Lopez, James Parker, Kunio Kosaka, Takumi Satoh, Scott R McKercher, Eliezer Masliah, Nobuki Nakanishi
Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27902447/a-unique-type-of-gsk-3-inhibitor-brings-new-opportunities-to-the-clinic
#2
Avital Licht-Murava, Rom Paz, Lilach Vaks, Limor Avrahami, Batya Plotkin, Miriam Eisenstein, Hagit Eldar-Finkelman
Development of protein kinase inhibitors is a focus of many drug discovery programs. A major problem, however, is the limited specificity of the commonly used adenosine triphosphate-competitive inhibitors and the weak inhibition of the more selective substrate-competitive inhibitors. Glycogen synthase kinase-3 (GSK-3) is a promising drug target for treating neurodegenerative disorders, including Alzheimer's disease (AD), but most GSK-3 inhibitors have not reached the clinic. We describe a new type of GSK-3 inhibitor, L807mts, that acts through a substrate-to-inhibitor conversion mechanism that occurs within the catalytic site of the enzyme...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902446/science-signaling-podcast-for-15-november-2016-a-new-type-of-kinase-inhibitor
#3
Hagit Eldar-Finkelman, Annalisa M VanHook
This Podcast features an interview with Hagit Eldar-Finkelman, author of a Research Article that appears in the 15 November 2016 issue of Science Signaling, about a newly developed inhibitor of glycogen synthase kinase 3 (GSK-3). GSK-3 participates in several signaling networks and has been implicated in various pathologies, including neurodegenerative diseases, cognitive impairments, and cancer. Licht-Murava et al developed L807mts, a substrate-competitive peptide inhibitor that blocks GSK-3 activity through an unusual mechanism...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27895577/fus1-ko-mouse-as-a-model-of-oxidative-stress-mediated-sporadic-alzheimer-s-disease-circadian-disruption-and-long-term-spatial-and-olfactory-memory-impairments
#4
Guillermo Coronas-Samano, Keeley L Baker, Winston J T Tan, Alla V Ivanova, Justus V Verhagen
Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology...
2016: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/27881781/blocking-the-interaction-between-ephb2-and-addls-by-a-small-peptide-rescues-impaired-synaptic-plasticity-and-memory-deficits-in-a-mouse-model-of-alzheimer-s-disease
#5
Xiao-Dong Shi, Kai Sun, Rui Hu, Xiao-Ya Liu, Qiu-Mei Hu, Xiao-Yu Sun, Bin Yao, Nan Sun, Jing-Ru Hao, Pan Wei, Yuan Han, Can Gao
: Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27881772/store-operated-calcium-channel-complex-in-postsynaptic-spines-a-new-therapeutic-target-for-alzheimer-s-disease-treatment
#6
Hua Zhang, Suya Sun, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Klementina Fon Tacer, Ilya Bezprozvanny
: Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca(2+) influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca(2+) channel complex in hippocampal mushroom spines...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27878757/targeting-ccr3-to-reduce-amyloid-%C3%AE-production-tau-hyperphosphorylation-and-synaptic-loss-in-a-mouse-model-of-alzheimer-s-disease
#7
Chunyan Zhu, Bing Xu, Xiaohong Sun, Qiwen Zhu, Yi Sui
The majority of Alzheimer's disease (AD) patients have a late onset, and chronic neuroinflammation, characterized by glial activation and secretion of pro-inflammatory cytokines and chemokines, plays a role in the pathogenesis of AD. The chemokine CCL11 has been shown to be a causative factor of cognitive decline in the process of aging, but little is known whether it is involved in the pathogenesis of AD. In the present study, we showed that CCR3, the receptor for CCL11, was expressed by hippocampal neurons and treatment of primary hippocampal neuronal cultures (14 days in vitro) with CCL11 resulted in activation of cyclin-dependent kinase 5 and glycogen synthase kinase-3β, associated with elevated tau phosphorylation at multiple sites...
November 23, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27875002/superparamagnetic-nanoparticle-enhanced-mri-of-alzheimer-s-disease-plaques-and-activated-microglia-in-3x-transgenic-mouse-brains-contrast-optimization
#8
Marissa A Tafoya, Saaussan Madi, Laurel O Sillerud
PURPOSE: To optimize magnetic resonance imaging (MRI) of antibody-conjugated superparamagnetic nanoparticles for detecting amyloid-β plaques and activated microglia in a 3X transgenic mouse model of Alzheimer's disease. MATERIALS AND METHODS: Ten 3X Tg mice were fed either chow or chow containing 100 ppm resveratrol. Four brains, selected from animals injected with either anti-amyloid targeted superparamagnetic iron oxide nanoparticles, or anti-Iba-1-conjugated FePt-nanoparticles, were excised, fixed with formalin, and placed in Fomblin for ex vivo MRI (11...
November 22, 2016: Journal of Magnetic Resonance Imaging: JMRI
https://www.readbyqxmd.com/read/27872583/ablation-of-sphingosine-1-phosphate-receptor-subtype-3-impairs-hippocampal-neuron-excitability-in-vitro-and-spatial-working-memory-in-vivo
#9
Daniela Weth-Malsch, Michiel Langeslag, Dimitra Beroukas, Luca Zangrandi, Iris Kastenberger, Serena Quarta, Philipp Malsch, Theodora Kalpachidou, Christoph Schwarzer, Richard L Proia, Rainer V Haberberger, Michaela Kress
Understanding the role of the bioactive lipid mediator sphingosine 1-phosphate (S1P) within the central nervous system has recently gained more and more attention, as it has been connected to major diseases such as multiple sclerosis and Alzheimer's disease. Even though much data about the functions of the five S1P receptors has been collected for other organ systems, we still lack a complete understanding for their specific roles, in particular within the brain. Therefore, it was the aim of this study to further elucidate the role of S1P receptor subtype 3 (S1P3) in vivo and in vitro with a special focus on the hippocampus...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27872019/metabotropic-glutamate-receptors-and-neurodegenerative-diseases
#10
REVIEW
Fabiola M Ribeiro, Luciene B Vieira, Rita G W Pires, Roenick P Olmo, Stephen S G Ferguson
Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation...
November 18, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27863809/efficacy-and-safety-of-tau-aggregation-inhibitor-therapy-in-patients-with-mild-or-moderate-alzheimer-s-disease-a-randomised-controlled-double-blind-parallel-arm-phase-3-trial
#11
Serge Gauthier, Howard H Feldman, Lon S Schneider, Gordon K Wilcock, Giovanni B Frisoni, Jiri H Hardlund, Hans J Moebius, Peter Bentham, Karin A Kook, Damon J Wischik, Bjoern O Schelter, Charles S Davis, Roger T Staff, Luc Bracoud, Kohkan Shamsi, John M D Storey, Charles R Harrington, Claude M Wischik
BACKGROUND: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease...
November 15, 2016: Lancet
https://www.readbyqxmd.com/read/27860527/roles-of-ppar-transcription-factors-in-the-energetic-metabolic-switch-occurring-during-adult-neurogenesis
#12
E Di Giacomo, E Benedetti, L Cristiano, A Antonosante, M d'Angelo, A Fidoamore, D Barone, S Moreno, R Ippoliti, M P Cerù, A Giordano, A Cimini
PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation...
November 18, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27857756/effects-of-triptolide-on-hippocampal-microglial-cells-and-astrocytes-in-the-app-ps1-double-transgenic-mouse-model-of-alzheimer-s-disease
#13
Jian-Ming Li, Yan Zhang, Liang Tang, Yong-Heng Chen, Qian Gao, Mei-Hua Bao, Ju Xiang, De-Liang Lei
The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile plaques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease...
September 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27857754/protective-effect-of-tetrahydroxy-stilbene-glucoside-on-learning-and-memory-by-regulating-synaptic-plasticity
#14
Hong-Bo Luo, Yun Li, Zun-Jing Liu, Li Cao, Zhi-Qiang Zhang, Yong Wang, Xiao-Yan Zhang, Zhao Liu, Xiang-Qun Shi
Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically...
September 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27853422/rock1-is-associated-with-alzheimer-s-disease-specific-plaques-as-well-as-enhances-autophagosome-formation-but-not-autophagic-a%C3%AE-clearance
#15
Yong-Bo Hu, Yang Zou, Yue Huang, Yong-Fang Zhang, Guinevere F Lourenco, Sheng-Di Chen, Glenda M Halliday, Gang Wang, Ru-Jing Ren
Alzheimer's disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27849045/deletion-of-neurotrophin-signaling-through-the-glucocorticoid-receptor-pathway-causes-tau-neuropathology
#16
Margarita Arango-Lievano, Camille Peguet, Matthias Catteau, Marie-Laure Parmentier, Synphen Wu, Moses V Chao, Stephen D Ginsberg, Freddy Jeanneteau
Glucocorticoid resistance is a risk factor for Alzheimer's disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27847962/the-multi-target-effects-of-cni-1493-convergence-of-anti-amylodogenic-and-anti-inflammatory-properties-in-animal-models-of-alzheimer-s-disease
#17
Roman Sankowski, Arne Herring, Kathy Keyvani, Kathrin Frenzel, Jinyu Wu, Stephan Röskam, Carmen Noelker, Michael Bacher, Yousef Al-Abed
After several decades of Alzheimer's disease (AD) research and failed clinical trials, one can speculate that targeting a single pathway is not sufficient. However, a cocktail of novel therapeutics will constitute a challenging clinical trial. A more plausible approach will capitalize on a drug that has relevant and synergistic multiple-target effects in AD. We have previously demonstrated the efficacy of CNI-1493 in the CRND8 transgenic AD mouse model. Similar to many anti-inflammatory drugs that were tested in preclinical model of AD, it was speculated that the significant effect of CNI-1493 is due to its established anti-inflammatory properties in rodents and humans...
November 15, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27842487/molecular-interactions-of-bexarotene-a-retinoid-drug-and-alzheimer-s-a%C3%AE-peptide-a-docking-study
#18
Zeenat Mirza, Mohd Amin Beg
Alzheimer's disease (AD) pathogenesis is primarily hallmarked by the production and accumulation of amyloid beta (Aβ) peptide. Along with the understanding of the neurodegenerative disease progression and its pathophysiological mechanisms, development of anti-Aβ targeted effective therapeutics is essential for AD management. Numerous therapeutic approaches targeting the production, toxicity and removal of Aβ are being attempted worldwide. Prime need is to design inhibitors which can slow down the Aβ aggregation process in a physiological environment...
November 14, 2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/27837334/mechanism-of-depression-as-a-risk-factor-in-the-development-of-alzheimer-s-disease-the-function-of-aqp4-and-the-glymphatic-system
#19
Maosheng Xia, Li Yang, Guangfeng Sun, Shuang Qi, Baoman Li
BACKGROUND: Many studies have indicated that a history of depression increases the risk of developing Alzheimer's disease (AD); however, the potential pathogenestic mechanism by which depression functions as a high risk factor for AD remains unknown. Recently, a "cerebral lymphatic system" referred to as "glymphatic system" has been demonstrated to be responsible for neuronal extracellular waste protein clearance via a paravascular pathway. However, the function of glymphatic pathway has not been determined in depressive disorders...
November 12, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27836896/reduced-nitric-oxide-bioavailability-mediates-cerebroarterial-dysfunction-independent-of-cerebral-amyloid-angiopathy-in-a-mouse-model-of-alzheimer-s-disease
#20
Mario Merlini, Yi Shi, Stephan Keller, Gianluigi Savarese, Alexander Akhmedov, Rebecca Derungs, Remo Daniel Spescha, Luka Kulic, Roger Nitsch, Thomas Lüscher, Giovanni Camici
In Alzheimer's disease (AD), cerebral arteries, in contrast to cerebral microvessels, show both cerebral amyloid angiopathy- (CAA) dependent and -independent vessel wall pathology. However, it remains unclear whether CAA-independent vessel wall pathology affects arterial function thereby chronically reducing cerebral perfusion, and if so which mechanisms mediate this effect. To this end, we assessed the ex vivo vascular function of the basilar artery and a similar-sized peripheral artery (femoral artery) in the Swedish-Arctic (SweArc) transgenic AD mouse model at different disease stages...
November 11, 2016: American Journal of Physiology. Heart and Circulatory Physiology
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