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Aggregation of deposits animal model

George Taylor-Walker, Savannah A Lynn, Eloise Keeling, Rosie Munday, David A Johnston, Anton Page, Jennifer A Scott, Srini Goverdhan, Andrew J Lotery, J Arjuna Ratnayaka
Age-related Macular Degeneration (AMD) is a common, irreversible blinding condition that leads to the loss of central vision. AMD has a complex aetiology with both genetic as well as environmental risks factors, and share many similarities with Alzheimer's disease. Recent findings have contributed significantly to unravelling its genetic architecture that is yet to be matched by molecular insights. Studies are made more challenging by observations that aged and AMD retinas accumulate the highly pathogenic Alzheimer's-related Amyloid beta (Aβ) group of peptides, for which there appears to be no clear genetic basis...
October 14, 2016: Experimental Eye Research
Ahmadali Sajadi, Chloé Provost, Brendon Pham, Jonathan Brouillette
Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans...
2016: Journal of Visualized Experiments: JoVE
Holger Cynis, Jeffrey L Frost, Helen Crehan, Cynthia A Lemere
Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms...
2016: Molecular Neurodegeneration
Ashok Verma
Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn)-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals...
April 2016: Annals of Indian Academy of Neurology
Natarajan Suganthy, Dicson Sheeja Malar, Kasi Pandima Devi
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by accumulation and deposition of Aβ peptide in human brain. The present study aimed to determine the protective effect of catechin rich extract of MERM (methanolic extract of Rhizophora mucronata) on Aβ (25-35) induced cognitive impairment and neuronal toxicity in mice. In the present study AD characteristics were induced by intracerberoventricular administration of aggregated Aβ (25-35) in the Swiss albino mice. Learning and memory deficits were assessed using behavioral assays such as Morris water maze, Y-maze and step down avoidance tasks...
August 2016: Metabolic Brain Disease
Michael J Yetman, Stephanie W Fowler, Joanna L Jankowsky
Alzheimer's disease (AD) researchers have struggled for decades to draw a causal link between extracellular Aβ aggregation and intraneuronal accumulation of microtubule-associated protein tau. The amyloid cascade hypothesis posits that Aβ deposition promotes tau hyperphosphorylation, tangle formation, cell loss, vascular damage, and dementia. While the genetics of familial AD and the pathological staging of sporadic disease support this sequence of events, attempts to examine the molecular mechanism in transgenic animal models have largely relied on models of other inherited tauopathies as the basis for testing the interaction with Aβ...
2016: PloS One
Johnny Habchi, Paolo Arosio, Michele Perni, Ana Rita Costa, Maho Yagi-Utsumi, Priyanka Joshi, Sean Chia, Samuel I A Cohen, Martin B D Müller, Sara Linse, Ellen A A Nollen, Christopher M Dobson, Tuomas P J Knowles, Michele Vendruscolo
The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively...
February 2016: Science Advances
Matthias Brendel, Anna Jaworska, Federico Probst, Felix Overhoff, Viktoria Korzhova, Simon Lindner, Janette Carlsen, Peter Bartenstein, Ryuichi Harada, Yukitsuka Kudo, Christian Haass, Fred Van Leuven, Nobuyuki Okamura, Jochen Herms, Axel Rominger
Abnormal accumulation of tau aggregates in the brain is one of the hallmarks of Alzheimer disease neuropathology. We visualized tau deposition in vivo with the previously developed 2-arylquinoline derivative (18)F-THK5117 using small-animal PET in conjunction with autoradiography and immunohistochemistry gold standard assessment in 2 transgenic mouse models expressing hyperphosphorylated tau. Small-animal PET recordings were obtained in groups of P301S (n = 11) and biGT mice (n = 16) of different ages, with age-matched wild-type (WT) serving as controls...
May 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Rina Bandopadhyay
Alpha-synuclein (α-syn) protein is abundantly expressed mainly within neurons, and exists in a number of different forms - monomers, tetramers, oligomers and fibrils. During disease, α-syn undergoes conformational changes to form oligomers and high molecular weight aggregates that tend to make the protein more insoluble. Abnormally aggregated α-syn is a neuropathological feature of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Biochemical characterization and analysis of insoluble α-syn using buffers with increasing detergent strength and high-speed ultracentrifugation provides a powerful tool to determine the development of α-syn pathology associated with disease progression...
2016: Journal of Visualized Experiments: JoVE
Peng Yuan, Jaime Grutzendler
UNLABELLED: Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate β-amyloid (Aβ) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown...
January 13, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Clair A Booth, Jonathan Witton, Jakub Nowacki, Krasimira Tsaneva-Atanasova, Matthew W Jones, Andrew D Randall, Jonathan T Brown
UNLABELLED: The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration...
January 13, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Salvador Ventura
A growing number of human diseases seem to be associated with protein misfolding and deposition into aggregates. Bednarska and colleagues exploit the cytotoxic nature of protein aggregates to target bacterial infections. Protein aggregation is at the same time generic and sequence dependent; this allowed the authors to develop novel aggregation-prone antimicrobial peptides that penetrate bacteria and induce a peptide specific proteostatic collapse that leads to fast bacterial death, without any observable effects on host cells...
March 2016: Molecular Microbiology
Hans Zempel, Eva-Maria Mandelkow
In Alzheimer Disease (AD), the mechanistic connection of the two major pathological hallmarks, namely deposition of Amyloid-beta (Aβ) in the form of extracellular plaques, and the pathological changes of the intracellular protein Tau (such as phosphorylation, missorting, aggregation), is not well understood. Genetic evidence from AD and Down Syndrome (Trisomy 21), and animal models thereof, suggests that aberrant production of Aβ is upstream of Tau aggregation, but also points to Tau as a critical effector in the pathological process...
2015: Molecular Neurodegeneration
Caihong Zhu, Petra Schwarz, Irina Abakumova, Adriano Aguzzi
Epidemiological, clinical, and experimental animal studies suggest a strong correlation between insulin resistance and Alzheimer's disease. In fact, type-2 diabetes is considered an important risk factor of developing Alzheimer's disease. In addition, impaired insulin signaling in the Alzheimer's disease brain may promote Aβ production, impair Aβ clearance and induce tau hyperphosphorylation, thereby leading to deterioration of the disease. The pathological prion protein, PrPSc, deposits in the form of extracellular aggregates and leads to dementia, raising the question as to whether prion pathogenesis may also be affected by insulin resistance...
2015: PloS One
Hye Yun Kim, Hyunjin Vincent Kim, Seonmi Jo, C Justin Lee, Seon Young Choi, Dong Jin Kim, YoungSoo Kim
Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes...
2015: Nature Communications
I V Zueva, V E Semenov, M A Mukhamedyarov, S V Lushchekina, A D Kharlamova, E O Petukhova, A S Mikhailov, S N Podyachev, L F Saifina, K A Petrov, O A Minnekhanova, V V Zobov, E E Nikolsky, P Masson, V S Reznik
BACKGROUND: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2]. Reduction of Aβ production and increasing clearance of Aβ pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment...
2015: International Journal of Risk & Safety in Medicine
Maliheh Soodi, Soodabeh Saeidnia, Mohammad Sharifzadeh, Homa Hajimehdipoor, Abolfazl Dashti, Mohammad Reza Sepand, Shahla Moradi
Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration...
April 2016: Metabolic Brain Disease
Yulin An, Wei wei, Huan Jing, Leiguo Ming, Shiyu Liu, Yan Jin
Cutaneous wounds are among the most common soft tissue injuries. Wounds involving dermis suffer more from outside influence and higher risk of chronic inflammation. Therefore the appearance and function restoration has become an imperative in tissue engineering research. In this study, cell-aggregates constructed with green fluorescent protein-expressing (GFP(+)) rat bone marrow mesenchymal stem cells (BMMSCs) were applied to rat acute full-layer cutaneous wound model to confirm its pro-regeneration ability and compare its regenerative efficacy with the currently thriving subcutaneous and intravenous stem cell administration strategy, with a view to sensing the advantages, disadvantages and the mechanism behind...
2015: Scientific Reports
Saki Ogawa, Tomoaki Murakami, Yasuo Inoshima, Naotaka Ishiguro
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments...
2015: Amyloid: the International Journal of Experimental and Clinical Investigation
Daryl Rhys Jones, Marion Delenclos, AnnMarie T Baine, Michael DeTure, Melissa E Murray, Dennis W Dickson, Pamela J McLean
The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process...
December 2015: Journal of Neuropathology and Experimental Neurology
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