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Aggregation of deposits animal model

Brent Race, Katie Williams, Andrew G Hughson, Casper Jansen, Piero Parchi, Annemieke J M Rozemuller, Bruce Chesebro
Human familial prion diseases are associated with mutations at 34 different prion protein (PrP) amino acid residues. However, it is unclear whether infectious prions are found in all cases. Mutant PrP itself may be neurotoxic, or alternatively, PrP mutation might predispose to spontaneous formation of infectious PrP isoforms. Previous reports demonstrated transmission to animal models by human brain tissue expressing 7 different PrP mutations, but 3 other mutations were not transmissible. In the present work, we tested transmission using brain homogenates from patients expressing 3 untested PrP mutants: G131V, Y226X, and Q227X...
February 20, 2018: Acta Neuropathologica Communications
Daniel Markx, Cornelia Loos, Stephanie Claus, Christian Haupt, Christian Mawrin, Marcus Fändrich
Intracerebral injection of brain extracts from Alzheimer's disease (AD) patients into appropriate mouse models was previously found to drastically accelerate the deposition of Aβ amyloid in the recipient animals indicating a prion-like activity. In this study we show that this prion-like activity can be also identified by using a cell culture model of Aβ plaque formation. Analysis of biochemical fractions of AD brain extract indicate that the seeding-activity correlated with the presence of Aβ peptide and Aβ-derived aggregates...
February 16, 2018: Biochemical and Biophysical Research Communications
Christophe Sirac, Guillermo A Herrera, Paul W Sanders, Vecihi Batuman, Sebastien Bender, Maria V Ayala, Vincent Javaugue, Jiamin Teng, Elba A Turbat-Herrera, Michel Cogné, Guy Touchard, Nelson Leung, Frank Bridoux
The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits...
February 19, 2018: Nature Reviews. Nephrology
Stéphane Peineau, Kevin Rabiant, Olivier Pierrefiche, Brigitte Potier
Synaptic plasticity is a cellular process involved in learning and memory whose alteration in its two main forms (Long Term Depression (LTD) and Long Term Potentiation (LTP)), is observed in most brain pathologies, including neurodegenerative disorders such as Alzheimer's disease (AD). In humans, AD is associated at the cellular level with neuropathological lesions composed of extracellular deposits of β-amyloid (Aβ) protein aggregates and intracellular neurofibrillary tangles, cellular loss, neuroinflammation and a general brain homeostasis dysregulation...
February 6, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Laura M Taylor, Pamela J McMillan, Nicole F Liachko, Timothy J Strovas, Bernardino Ghetti, Thomas D Bird, C Dirk Keene, Brian C Kraemer
BACKGROUND: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients...
February 6, 2018: Molecular Neurodegeneration
J K Chang, A Leso, G M Subaiea, A Lahouel, A Masoud, F Mushtaq, R Deeb, A Eid, M Dash, S W Bihaqi, N H Zawia
OBJECTIVE: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer's disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share in common cortical lesions composed of aggregates of the protein tau. METHODS: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau)...
January 18, 2018: Current Alzheimer Research
Colin F Greineder, Ian H Johnston, Carlos H Villa, Kandace Gollomp, Charles T Esmon, Douglas B Cines, Mortimer Poncz, Vladimir R Muzykantov
Diverse human illnesses are characterized by loss or inactivation of endothelial thrombomodulin (TM), predisposing to microvascular inflammation, activation of coagulation, and tissue ischemia. Single-chain antibody fragment (scFv)/TM) fusion proteins, previously protective against end-organ injury in murine models of inflammation, are attractive candidates to treat inflammatory thrombosis. However, animal models have inherent differences in TM and coagulation biology, are limited in their ability to resolve and control endothelial biology, and do not allow in-depth testing of "humanized" scFv/TM fusion proteins, which are necessary for translation to the clinical domain...
August 8, 2017: Blood Advances
Frances C Bach, Lisanne T Laagland, Michael P Grant, Laura B Creemers, Keita Ito, Björn P Meij, Fackson Mwale, Marianna A Tryfonidou
INTRODUCTION: Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells...
2017: PloS One
Neha Sharma, Bimla Nehru
Parkinson's disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure...
October 12, 2017: Inflammopharmacology
Nobuyuki Kato, Yasuto Mastui, Masaki Takaoka, Minoru Yoneda
OBJECTIVES: Nanoparticles (NPs), including hazardous substances, are generated in crematoriums due to the high temperatures during the combustion process. NPs are reported to greatly impact animals' health by reaching the alveoli and being carried to the entire body through the blood stream. However, studies in crematoriums have yet to assess workers' exposure to the generated NPs. The purpose of this study is to assess workers' exposure to NPs released in crematoriums. METHODS: Field surveys were conducted in three crematoriums with an emphasis on cremation, bone rearrangement and cleaning processes...
November 25, 2017: Journal of Occupational Health
Kaori Takahashi-Ito, Mitsuhiro Makino, Keiko Okado, Taisuke Tomita
Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble β-amyloid (Aβ) and soluble Aβ oligomers in animal models of AD. The mechanisms by which memantine reduces Aβ levels in the brain were evaluated by determining the effect of memantine on Aβ aggregation using thioflavin T and transmission electron microscopy...
November 4, 2017: Biochemical and Biophysical Research Communications
Ramona F Sowade, Thomas R Jahn
Seeded propagation of amyloid-beta (Aβ) pathology is suggested to contribute to the progression of Alzheimer's disease. Local overproduction of aggregation-prone Aβ variants could explain the focal initiation of a seeding cascade that subsequently triggers widespread pathology. Several animal models support this seeding concept by demonstrating accelerated Aβ deposition following inoculation with Aβ-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study Aβ seeding processes in vivo using Drosophila models...
September 11, 2017: Nature Communications
Ian Diner, Jeromy Dooyema, Marla Gearing, Lary C Walker, Nicholas T Seyfried
The benzothiazole-aniline derivative Pittsburgh Compound B (PiB) is the prototypical amyloid affinity probe developed for the in vivo positron emission tomography (PET) detection of amyloid beta (Aβ) deposits in Alzheimer's disease (AD). Specific high-affinity binding sites for PiB have been found to vary among AD cases with comparable Aβ load, and they are virtually absent on human-sequence Aβ deposits in animal models, none of which develop the full phenotype of AD. PiB thus could be an informative probe for studying the pathobiology of Aβ, but little is known about the localization of PiB binding at the molecular or structural level...
October 18, 2017: Bioconjugate Chemistry
Hai-Yan Xing, Bin Li, Dan Peng, Chun-Yan Wang, Guan-Ying Wang, Pan Li, Ying-Ying Le, Ji-Ming Wang, George Ye, Jian-Hong Chen
Senile plaques consisting of Amyloid-beta (Aβ) peptides, in particular Aβ1-42, are the hallmark of Alzheimer's disease (AD) and have been the primary therapeutic targets. Passive immunotherapy with monoclonal antibodies (mAbs) has shown initial success in mouse models of AD. However, the existing Aβ-directed mAbs mostly were tested on animal models or patients with advanced disease. The effects and mechanisms of mAbs on animals or human trial participants in the prodromal phase of AD are not fully clarified...
2017: PloS One
Junling Yang, Jinghong Kou, Robert Lalonde, Ken-Ichiro Fukuchi
Neuroinflammation is a pervasive feature of Alzheimer's disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid β protein (Aβ). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery...
October 2017: Brain, Behavior, and Immunity
E Orta-Salazar, A I Feria-Velasco, S Díaz-Cintra
INTRODUCTION: In humans and animal models, Alzheimer disease (AD) is characterised by accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, neuronal degeneration, and astrocytic gliosis, especially in vulnerable brain regions (hippocampus and cortex). These alterations are associated with cognitive impairment (loss of memory) and non-cognitive impairment (motor impairment). The purpose of this study was to identify cell changes (neurons and glial cells) and aggregation of Aβ and hyperphosphorylated tau protein in the primary motor cortex (M1) in 3xTg-AD mouse models at an intermediate stage of AD...
April 19, 2017: Neurología: Publicación Oficial de la Sociedad Española de Neurología
Giovanni L Romano, Chiara B M Platania, Filippo Drago, Salvatore Salomone, Marco Ragusa, Cristina Barbagallo, Cinzia Di Pietro, Michele Purrello, Michele Reibaldi, Teresio Avitabile, Antonio Longo, Claudio Bucolo
Age related macular degeneration (AMD) is the leading cause of blindness among people aged 50 and over. Retinal deposition of amyloid-β (Aβ) aggregates in AMD patients has suggested a potential link between AMD and Alzheimer's disease (AD). We have evaluated the differential retinal expression profile of miRNAs in a rat model of AMD elicited by Aβ. A serum profile of miRNAs in AMD patients has been also assessed using single TaqMan assay. Analysis of retina from rats intravitreally injected with Aβ revealed that miR-27a, miR-146a, and miR-155 were up-regulated in comparison to control rats...
2017: Frontiers in Pharmacology
Meredith E Jackrel, James Shorter
Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function...
2017: Frontiers in Neuroscience
Alina Hategan, Mario A Bianchet, Joseph Steiner, Elena Karnaukhova, Eliezer Masliah, Adam Fields, Myoung-Hwa Lee, Alex M Dickens, Norman Haughey, Emilios K Dimitriadis, Avindra Nath
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance...
April 2017: Nature Structural & Molecular Biology
Valerija Kovač, Blaž Zupančič, Gregor Ilc, Janez Plavec, Vladka Čurin Šerbec
In the brain of patients with transmissible spongiform encephalopathies, besides PrP(Sc) aggregates, deposition of truncated PrP molecules was described. Jansen et al. reported two clinical cases with deposition of C-terminally truncated PrP, one of them ending with Tyr226. We have previously described the discovery of monoclonal antibody V5B2 that selectively recognizes this version of the prion protein, which we called PrP226*. Using monoclonal antibody V5B2 we showed that accumulation of PrP226* is characteristic for most types of human and animal TSEs...
February 26, 2017: Biochemical and Biophysical Research Communications
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