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Mouse modell for alzheimers disease

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https://www.readbyqxmd.com/read/28923083/prevention-of-c5ar1-signaling-delays-microglial-inflammatory-polarization-favors-clearance-pathways-and-suppresses-cognitive-loss
#1
Michael X Hernandez, Shan Jiang, Tracy A Cole, Shu-Hui Chu, Maria I Fonseca, Melody J Fang, Lindsay A Hohsfield, Maria D Torres, Kim N Green, Rick A Wetsel, Ali Mortazavi, Andrea J Tenner
BACKGROUND: Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28922421/effects-of-acute-administration-of-donepezil-or-memantine-on-sleep-deprivation-induced-spatial-memory-deficit-in-young-and-aged-non-human-primate-grey-mouse-lemurs-microcebus-murinus
#2
Anisur Rahman, Yves Lamberty, Esther Schenker, Massimo Cella, Solène Languille, Régis Bordet, Jill Richardson, Fabien Pifferi, Fabienne Aujard
The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation...
2017: PloS One
https://www.readbyqxmd.com/read/28922152/brain-biomarkers-in-familial-alzheimer-s-disease-mouse-models
#3
Yafit Kuttner-Hirshler, Palamadai N Venkatasubramanian, Joan Apolinario, Jacqueline Bonds, Alice M Wyrwicz, Orly Lazarov
Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer's disease (FAD)...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28922151/dickkopf-3-dkk3-improves-amyloid-%C3%AE-pathology-cognitive-dysfunction-and-cerebral-glucose-metabolism-in-a-transgenic-mouse-model-of-alzheimer-s-disease
#4
Li Zhang, Caixian Sun, Yaxi Jin, Kai Gao, Xudong Shi, Wenying Qiu, Chao Ma, Lianfeng Zhang
Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28919467/distribution-of-spleen-tyrosine-kinase-and-tau-phosphorylated-at-tyrosine-18-in-a-mouse-model-of-tauopathy-and-in-the-human-hippocampus
#5
Christoph Köhler, Vivien Timpa, Maja Dinekov
PURPOSE: Spleen tyrosine kinase (Syk) has been shown to phosphorylate tyrosine 18 of tau in vitro. It has been proposed that increased immunoreactivity for double-phosphorylated Syk in hippocampal neurons of Alzheimer's disease cases indicates a not yet defined neurodegenerative process. To investigate this possibility we have studied Syk and tau phosphorylated at tyrosine 18 (pTyr18) in transgenic mice and human hippocampi. METHODS: We performed immunohistochemistry, immunofluorescence labeling and Western blotting and compared the distribution of Syk double-phosphorylated at tyrosines 525 and 526 and pTyr18 in human tau transgenic pR5 mice and human hippocampi with low and high Braak stages for neurofibrillary tangle pathology...
September 14, 2017: Brain Research
https://www.readbyqxmd.com/read/28917978/sen1500-a-novel-oral-amyloid-%C3%AE-aggregation-inhibitor-attenuates-brain-pathology-in-a-mouse-model-of-alzheimer-s-disease
#6
D Brunner, S Flunkert, J Neddens, S Duller, D I C Scopes, J M Treherne, B Hutter-Paier
INTRODUCTION: Amyloid-β (Aβ) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the Aβ aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Aβ aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain Aβ pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APPSL)...
September 13, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28912896/investigation-of-the-safety-of-focused-ultrasound-induced-blood-brain-barrier-opening-in-a-natural-canine-model-of-aging
#7
Meaghan Anne O'Reilly, Ryan Matthew Jones, Edward Barrett, Anthony Schwab, Elizabeth Head, Kullervo Hynynen
Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits...
2017: Theranostics
https://www.readbyqxmd.com/read/28912154/inhibition-of-p25-cdk5-attenuates-tauopathy-in-mouse-and-ipsc-models-of-frontotemporal-dementia
#8
Jinsoo Seo, Oleg Kritskiy, L Ashley Watson, Scarlett J Barker, Dilip Dey, Waseem K Raja, Yuan-Ta Lin, Tak Ko, Sukhee Cho, Jay Penney, M Catarina Silva, Steven D Sheridan, Diane Lucente, James F Gusella, Bradford C Dickerson, Stephen J Haggarty, Li-Huei Tsai
Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders including Alzheimer's disease (AD). Previously, we showed that replacing endogenous p35 with the non-cleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial AD mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28904096/ripk1-mediates-a-disease-associated-microglial-response-in-alzheimer-s-disease
#9
Dimitry Ofengeim, Sonia Mazzitelli, Yasushi Ito, Judy Park DeWitt, Lauren Mifflin, Chengyu Zou, Sudeshna Das, Xian Adiconis, Hongbo Chen, Hong Zhu, Michelle A Kelliher, Joshua Z Levin, Junying Yuan
Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro...
September 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28901737/melatonin-improves-cognitive-deficits-via-restoration-of-cholinergic-dysfunction-in-a-mouse-model-of-scopolamine-induced-amnesia
#10
Bai Hui Chen, Joon Ha Park, Dae Won Kim, Jinseu Park, Soo Young Choi, In Hye Kim, Jeong Hwi Cho, Tae-Kyeong Lee, Jae Chul Lee, Choong-Hyun Lee, In Koo Hwang, Young-Myeong Kim, Bing Chun Yan, Il-Jun Kang, Bich Na Shin, Yun Lyul Lee, Myoung Cheol Shin, Jun Hwi Cho, Young Joo Lee, Yong Hwan Jeon, Moo-Ho Won, Ji Hyeon Ahn
Melatonin is known to improve cognitive deficits and its functions have been studied in various disease models, including Alzheimer's disease. In this study, we investigated effects of melatonin on cognition and the cholinergic system of the septum and hippocampus in a mouse model of scopolamine-induced amnesia. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were administered intraperitoneally to mice for 2 and 4 weeks. The Morris water maze and passive avoidance tests revealed that both treatments of scopolamine significantly impaired spatial learning and memory; however, 2- and 4-week melatonin treatments significantly improved the spatial learning and memory...
September 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28899417/serotonin-augmentation-therapy-by-escitalopram-has-minimal-effects-on-amyloid-%C3%AE-levels-in-early-stage-alzheimer-s-like-disease-in-mice
#11
Christian Ulrich von Linstow, Jonas Waider, Manuela Grebing, Athanasios Metaxas, Klaus Peter Lesch, Bente Finsen
BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer's disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology...
September 12, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28899010/modelling-apoe-%C3%A9-3-4-allele-associated-sporadic-alzheimer-s-disease-in-an-induced-neuron
#12
Hongwon Kim, Junsang Yoo, Jaein Shin, Yujung Chang, Junghyun Jung, Dong-Gyu Jo, Janghwan Kim, Wonhee Jang, Christopher J Lengner, Byung-Soo Kim, Jongpil Kim
The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) ɛ3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ɛ3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-β42 and hyperphosphorylation of tau...
August 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28890389/motor-function-deficits-in-the-12-month-old-female-5xfad-mouse-model-of-alzheimer-s-disease
#13
T P O'Leary, A Robertson, P H Chipman, V F Rafuse, R E Brown
Motor problems occur early in some patients with Alzheimer's disease (AD) and as the disease progresses many patients develop motor dysfunction. Motor dysfunction has been reported in some mouse models of AD, including the 5xFAD mouse, thus this model may be particularly useful for studying motor dysfunction in AD. In order to determine the extent of motor dysfunction in these mice, we tested 11-13 month old female 5xFAD and wildtype (WT) control mice in a battery of motor behaviour tasks. The 5xFAD mice showed hind limb clasping, weighed less and had slower righting reflexes than WT mice...
September 7, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28890316/iron-biochemistry-is-correlated-with-amyloid-plaque-morphology-in-an-established-mouse-model-of-alzheimer-s-disease
#14
Neil D Telling, James Everett, Joanna F Collingwood, Jon Dobson, Gerrit van der Laan, Joseph J Gallagher, Jian Wang, Adam P Hitchcock
A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aβ...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28887195/pharmacological-activation-of-the-nrf2-pathway-by-3h-1-2-dithiole-3-thione-is-neuroprotective-in-a-mouse-model-of-alzheimer-disease
#15
YuanBo Cui, ShanShan Ma, ChunYan Zhang, DongPeng Li, Bo Yang, PengJu Lv, Qu Xing, Tuanjie Huang, Greta Luyuan Yang, Wei Cao, FangXia Guan
Accumulating evidence suggests that oxidative stress induced by beta-amyloid (Aβ) is implicated in the pathlogical progression of Alzheimer's disease (AD). 3H-1,2-dithiole-3-thione (D3T), the simplest compound of the sulfur-containing dithiolethiones, has been proved to be a strongly active antioxidant factor by regulation of the nuclear factor E2-related factor 2 (Nrf2). Previous study reported that D3T confers protection to AD cell model in vitro, however, the neuroprotective effect of D3T in the AD mammalian model is unknown...
September 6, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28886753/depletion-of-adult-neurogenesis-exacerbates-cognitive-deficits-in-alzheimer-s-disease-by-compromising-hippocampal-inhibition
#16
Carolyn Hollands, Matthew Kyle Tobin, Michael Hsu, Kianna Musaraca, Tzong-Shiue Yu, Rachana Mishra, Steven G Kernie, Orly Lazarov
BACKGROUND: The molecular mechanism underlying progressive memory loss in Alzheimer's disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer's disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis...
September 8, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28886007/microglia-emerge-as-central-players-in-brain-disease
#17
REVIEW
Michael W Salter, Beth Stevens
There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity...
September 8, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28885485/alterations-in-endocytic-protein-expression-with-increasing-age-in-the-transgenic-app695-v717i-london-mouse-model-of-amyloid-pathology-implications-for-alzheimer-s-disease
#18
Rhian S Thomas, Mouhamed Alsaqati, Justin S Bice, Martha Hvoslef-Eide, Mark A Good, Emma J Kidd
A major risk factor for the development of Alzheimer's disease (AD) is increasing age, but the reason behind this association has not been identified. It is thought that the changes in endocytosis seen in AD patients are causal for this condition. Thus, we hypothesized that the increased risk of developing AD associated with ageing may be because of changes in endocytosis. We investigated using Western blotting whether the expression of endocytic proteins involved in clathrin-mediated and clathrin-independent endocytosis are altered by increasing age in a mouse model of amyloid pathology...
September 6, 2017: Neuroreport
https://www.readbyqxmd.com/read/28882786/exosomal-biomarkers-in-down-syndrome-and-alzheimer-s-disease
#19
REVIEW
Eric D Hamlett, Aurélie Ledreux, Huntington Potter, Heidi J Chial, David Patterson, Joaquin M Espinosa, Brianne M Bettcher, Ann-Charlotte Granholm
Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood...
September 4, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28882308/the-use-of-mouse-models-to-study-cell-to-cell-transmission-of-pathological-tau
#20
Sneha Narasimhan, Virginia M Y Lee
Tau protein aggregates are found in a variety of neurodegenerative diseases known as tauopathies. Emerging evidence shows tau can propagate from cell-to-cell by seeding endogenous tau to aggregate. Studies in tau transgenic mice showed intracerebrally injecting misfolded tau seeds initiates and transmits tau pathology across the mouse brain. However, transgenic mice that overexpress human tau with disease-associated mutations do not fully recapitulate sporadic tauopathies. Here, we present our method for developing a sporadic tauopathy model using pathological tau extracted from human Alzheimer's disease (AD) brains...
2017: Methods in Cell Biology
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