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Mouse modell for alzheimers disease

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https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#1
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29782315/tlr4-gene-expression-and-pro-inflammatory-cytokines-in-alzheimer-s-disease-and-in-response-to-hippocampal-deafferentation-in-rodents
#2
Justin Miron, Cynthia Picard, Josée Frappier, Doris Dea, Louise Théroux, Judes Poirier
One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0...
May 16, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29778899/dopamine-loss-alters-the-hippocampus-nucleus-accumbens-synaptic-transmission-in-the-tg2576-mouse-model-of-alzheimer-s-disease
#3
Alberto Cordella, Paraskevi Krashia, Annalisa Nobili, Annabella Pignataro, Livia La Barbera, Maria Teresa Viscomi, Alessandro Valzania, Flavio Keller, Martine Ammassari-Teule, Nicola Biagio Mercuri, Nicola Berretta, Marcello D'Amelio
The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD...
May 17, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29775624/characterization-and-comparative-analysis-of-a-new-mouse-microglial-cell-model-for-studying-neuroinflammatory-mechanisms-during-neurotoxic-insults
#4
Souvarish Sarkar, Emir Malovic, Deeksha Sarda, Vivek Lawana, Dharmin Rokad, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
Microglia are the first responders of the central nervous system, acting as the key modulators of neuroinflammation observed during neurotoxic insults as well as in the pathophysiology of several neurodegenerative disorders including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD). The number of publications on microglia has increased steadily throughout the past decade because of immense interests in the neuroinflammation that precedes the neurodegenerative process. To study microglial biology and its role in modulating neuroinflammation, immortalized microglial cell lines derived from mice, rats, and humans have been developed...
May 15, 2018: Neurotoxicology
https://www.readbyqxmd.com/read/29774516/periodic-variation-of-aak1-in-an-a%C3%AE-1-42-induced-mouse-model-of-alzheimer-s-disease
#5
Xue Fu, Meiling Ke, Weihua Yu, Xia Wang, Qian Xiao, Min Gu, Yang Lü
Inhibition of endocytosis in an Alzheimer's disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ1-42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ1-42 -induced cognition changes...
May 17, 2018: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29770957/first-in-rat-study-of-human-alzheimer-s-disease-tau-propagation
#6
Tomas Smolek, Santosh Jadhav, Veronika Brezovakova, Veronika Cubinkova, Bernadeta Valachova, Petr Novak, Norbert Zilka
One of the key features of misfolded tau in human neurodegenerative disorders is its propagation from one brain area into many others. In the last decade, in vivo tau spreading has been replicated in several mouse transgenic models expressing mutated human tau as well as in normal non-transgenic mice. In this study, we demonstrate for the first time that insoluble tau isolated from human AD brain induces full-blown neurofibrillary pathology in a sporadic rat model of tauopathy expressing non-mutated truncated tau protein...
May 16, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29765479/protective-effects-of-evodiamine-in-experimental-paradigm-of-alzheimer-s-disease
#7
Dongmei Wang, Chenying Wang, Ling Liu, Sanqiang Li
Evodiamine, a major component of  Evodia rutaecarpa , has been reported to possess various pharmacological activities, including anti-inflammatory, antioxidative stress, and neuroprotective effects. Our previous study has shown that the potential effects of evodiamine on the learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). The present study was designed to investigate neuroprotective mechanism and therapeutic potential of evodiamine against intracerebroventricular streptozotocin (ICV-STZ)-induced experimental sporadic Alzheimer's disease in mice...
June 2018: Cognitive Neurodynamics
https://www.readbyqxmd.com/read/29764453/ampa-ergic-regulation-of-amyloid-%C3%AE-levels-in-an-alzheimer-s-disease-mouse-model
#8
Jane C Hettinger, Hyo Lee, Guojun Bu, David M Holtzman, John R Cirrito
BACKGROUND: Extracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms...
May 15, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29762014/selective-and-sensitive-pull-down-of-amyloid-fibrils-produced-in-vitro-and-in-vivo-by-the-use-of-pentameric-thiophene-coupled-resins
#9
Anna Beatriz Wreden, Luiza Fernandes, Mirian Kelley, Antônio Pereira-Neves, Caroline S Moreira, David R da Rocha, Fernando L Palhano
Protein aggregation is a hallmark of several degenerative diseases, including Alzheimer's disease, Parkinson's disease and familial amyloidosis (Finnish type) (FAF). A method to isolate and detect amyloids is desired for the diagnosis of amyloid diseases. Here, we report the synthesis of pentameric thiophene amyloid ligand (p-FTAA) linked to agarose resin for selective purification of amyloid aggregates produced in vitro and in vivo. Using amyloid fibrils produced in vitro from alpha-synuclein, gelsolin and Aβ1-40 and gelsolin amyloid aggregates extracted from tissue homogenates of a mouse model of FAF, we observed that p-FTAA resin was able to pull down amyloid aggregates...
May 15, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29758264/anti-il17-treatment-ameliorates-down-syndrome-phenotypes-in-mice
#10
Noemí Rueda, Verónica Vidal, Susana García-Cerro, Josep Oriol Narcís, María Llorens-Martín, Andrea Corrales, Sara Lantigua, Marcos Iglesias, Jesús Merino, Ramón Merino, Carmen Martínez-Cué
Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology...
May 11, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29743517/identification-of-new-epha4-inhibitors-by-virtual-screening-of-fda-approved-drugs
#11
Shuo Gu, Wing-Yu Fu, Amy K Y Fu, Estella Pui Sze Tong, Fanny C F Ip, Xuhui Huang, Nancy Y Ip
The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29740382/circadian-rhythm-dysfunction-accelerates-disease-progression-in-a-mouse-model-with-amyotrophic-lateral-sclerosis
#12
Zhilin Huang, Qiang Liu, Yu Peng, Jiaying Dai, Youna Xie, Weineng Chen, Simei Long, Zhong Pei, Huanxing Su, Xiaoli Yao
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by interactions between environmental factors and genetic susceptibility. Circadian rhythm dysfunction (CRD) is a significant contributor to neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. However, whether CRD contributes to the progression of ALS remains little known. We performed behavioral and physiological tests on SOD1G93A ALS model mice with and without artificially induced CRD, and on wild-type controls; we also analyzed spinal cord samples histologically for differences between groups...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29736028/pm20d1-is-a-quantitative-trait-locus-associated-with-alzheimer-s-disease
#13
Jose V Sanchez-Mut, Holger Heyn, Bianca A Silva, Lucie Dixsaut, Paula Garcia-Esparcia, Enrique Vidal, Sergi Sayols, Liliane Glauser, Ana Monteagudo-Sánchez, Jordi Perez-Tur, Isidre Ferrer, David Monk, Bernard Schneider, Manel Esteller, Johannes Gräff
The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors 1 , the latter likely being mediated by epigenetic mechanisms 2 . In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology 3 , but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS 4 ...
May 7, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29735432/the-retina-as-a-window-to-early-dysfunctions-of-alzheimer-s-disease-following-studies-with-a-5xfad-mouse-model
#14
Chiara Criscuolo, Elisa Cerri, Carlotta Fabiani, Simona Capsoni, Antonino Cattaneo, Luciano Domenici
Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to neuronal dysfunctions with cognitive impairment. AD can affect visual pathways and visual cortex and result in various visual changes and problems. However, how early the visual dysfunctions occur in AD is still a matter of discussion. Here, we used electrophysiological techniques to show the presence of early anomalies in AD visual system. To this aim, we used a familial AD (FAD) model, the 5xFAD transgenic mouse, characterized by severe progressive amyloid pathology and cognitive deficits...
March 23, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29733614/rational-design-of-novel-1-3-oxazine-based-%C3%AE-secretase-bace1-inhibitors-incorporation-of-a-double-bond-to-reduce-p-gp-efflux-leading-to-robust-a%C3%AE-reduction-in-the-brain
#15
Kouki Fuchino, Yasunori Mitsuoka, Moriyasu Masui, Noriyuki Kurose, Shuhei Yoshida, Kazuo Komano, Takahiko Yamamoto, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanoro Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Hirofumi Miyajima, Shuichi Hiroyama, Kiyotaka Koyabu, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
Accumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydo-oxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a pKa lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models...
May 7, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29731975/deletion-of-plasma-phospholipid-transfer-protein-pltp-increases-microglial-phagocytosis-and-reduces-cerebral-amyloid-%C3%AE-deposition-in-the-j20-mouse-model-of-alzheimer-s-disease
#16
Marine Mansuy, Stella Baille, Geoffrey Canet, Amélie Borie, Catherine Cohen-Solal, Michel Vignes, Véronique Perrier, Nathalie Chevallier, Naig Le Guern, Valérie Deckert, Laurent Lagrost, Laurent Givalois, Catherine Desrumaux
Plasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, cholesterol, diacylglycerides, tocopherols and lipopolysaccharides. PLTP functions are relevant for many pathophysiological alterations involved in neurodegenerative disorders (especially lipid metabolism, redox status, and immune reactions), and a significant increase in brain PLTP levels was observed in patients with Alzheimer's disease (AD) compared to controls. To date, it has not been reported whether PLTP can modulate the formation of amyloid plaques, i...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29729422/genetically-reducing-mtor-signaling-rescues-central-insulin-dysregulation-in-a-mouse-model-of-alzheimer-s-disease
#17
Antonella Caccamo, Ramona Belfiore, Salvatore Oddo
Alzheimer's disease (AD) is the most common neurodegenerative disease. The causes of sporadic AD, which represents more than 95% of AD cases, are unknown. Several AD risk factors have been identified and among these, type 2 diabetes increases the risk of developing AD by 2-fold. However, the mechanisms by which diabetes contributes to AD pathogenesis remain elusive. The mammalian target of rapamycin (mTOR) is a protein kinase that plays a crucial role in the insulin signaling pathway and has been linked to AD...
April 5, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29728702/elevated-levels-of-brain-homocysteine-directly-modulate-the-pathological-phenotype-of-a-mouse-model-of-tauopathy
#18
Antonio Di Meco, Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy...
May 4, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29728560/generation-of-app-knock-in-mice-reveals-deletion-mutations-protective-against-alzheimer-s-disease-like-pathology
#19
Kenichi Nagata, Mika Takahashi, Yukio Matsuba, Fumi Okuyama-Uchimura, Kaori Sato, Shoko Hashimoto, Takashi Saito, Takaomi C Saido
Although, a number of pathogenic mutations have been found for Alzheimer's disease (AD), only one protective mutation has been identified so far in humans. Here we identify possible protective deletion mutations in the 3'-UTR of the amyloid precursor protein (App) gene in mice. We use an App knock-in mouse model carrying a humanized Aβ sequence and three AD mutations in the endogenous App gene. Genome editing of the model zygotes using multiple combinations of CRISPR/Cas9 tools produces genetically mosaic animals with various App 3'-UTR deletions...
May 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29723637/multidimensional-co-segmentation-of-longitudinal-brain-mri-ensembles-in-the-presence-of-a-neurodegenerative-process
#20
Shiri Gordon, Irit Dolgopyat, Itamar Kahn, Tammy Riklin Raviv
MRI Segmentation of a pathological brain poses a significant challenge, as the available anatomical priors that provide top-down information to aid segmentation are inadequate in the presence of abnormalities. This problem is further complicated for longitudinal data capturing impaired brain development or neurodegenerative conditions, since the dynamic of brain atrophies has to be considered as well. For these cases, the absence of compatible annotated training examples renders the commonly used multi-atlas or machine-learning approaches impractical...
April 30, 2018: NeuroImage
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