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https://www.readbyqxmd.com/read/28538692/exploring-anti-prion-glyco-based-and-aromatic-scaffolds-a-chemical-strategy-for-the-quality-of-life
#1
REVIEW
María Teresa Blázquez-Sánchez, Ana M de Matos, Amélia P Rauter
Prion diseases are fatal neurodegenerative disorders caused by protein misfolding and aggregation, affecting the brain progressively and consequently the quality of life. Alzheimer's is also a protein misfolding disease, causing dementia in over 40 million people worldwide. There are no therapeutics able to cure these diseases. Cellular prion protein is a high-affinity binding partner of amyloid β (Aβ) oligomers, the most toxic species in Alzheimer's pathology. These findings motivate the development of new chemicals for a better understanding of the events involved...
May 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28538095/high-resolution-structures-of-the-amyloid-%C3%AE-1-42-dimers-from-the-comparison-of-four-atomistic-force-fields
#2
Viet Hoang Man, Phuong Hoang Nguyen, Philippe Derreumaux
The dimer of the amyloid-beta peptide Aβ of 42 residues is the smallest toxic species in Alzheimer's disease, but its equilibrium structures are unknown. Here we determined the equilibrium ensembles generated by the four atomistic OPLS-AA, CHARMM22*, AMBER99sb-ildn and AMBERsb14 force fields with the TIP3P water model. Based on 144 microsecond replica exchange molecular dynamics simulations (with 750 ns per replica), we find that the four force fields lead to random coil ensembles with calculated cross-collision sections, hydrodynamics properties and small-angle X-ray scattering profiles independent on the force field...
May 24, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28534084/the-emerging-link-between-o-glcnacylation-and-neurological-disorders
#3
REVIEW
Xiaofeng Ma, He Li, Yating He, Junwei Hao
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders...
May 22, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28533388/selective-lowering-of-synapsins-induced-by-oligomeric-%C3%AE-synuclein-exacerbates-memory-deficits
#4
Megan E Larson, Susan J Greimel, Fatou Amar, Michael LaCroix, Gabriel Boyle, Mathew A Sherman, Hallie Schley, Camille Miel, Julie A Schneider, Rakez Kayed, Fabio Benfenati, Michael K Lee, David A Bennett, Sylvain E Lesné
Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533191/mir-34a-knockout-attenuates-cognitive-deficits-in-app-ps1-mice-through-inhibition-of-the-amyloidogenic-processing-of-app
#5
Chongdong Jian, Mengru Lu, Zhao Zhang, Long Liu, Xianfeng Li, Fang Huang, Ning Xu, Lina Qin, Qian Zhang, Donghua Zou
The noncoding miRNA-34a (miR-34a) is involved in Alzheimer's disease (AD) pathologenesis and shows potential for application as a biomarker for early diagnosis and intervention. Here, we established miR-34a knockout mice in an APP/PS1 background (APP/PS1-miR-34a KO mice) by crossbreeding miR-34a(-/-) mice with APP/PS1 mice. We then investigated cognitive impairment and related pathologies. The results showed that the level of miR-34a was increased at about 6months in APP/PS1 mice, consistent with the increase in amyloid β (Aβ), and cognitive function was significantly improved in mice when miR-34a was knocked out in 9-month-old and 12-month-old mice, indicating that miR-34a is a potential candidate for determining the progression of AD...
May 19, 2017: Life Sciences
https://www.readbyqxmd.com/read/28531131/the-role-of-interleukin-18-oxidative-stress-and-metabolic-syndrome-in-alzheimer-s-disease
#6
REVIEW
Johanna O Ojala, Elina M Sutinen
The role of interleukins (ILs) and oxidative stress (OS) in precipitating neurodegenerative diseases including sporadic Alzheimer's disease (AD), requires further clarification. In addition to neuropathological hallmarks-extracellular neuritic amyloid-β (Aβ) plaques, neurofibrillary tangles (NFT) containing hyperphosphorylated tau and neuronal loss-chronic inflammation, as well as oxidative and excitotoxic damage, are present in the AD brain. The pathological sequelae and the interaction of these events during the course of AD need further investigation...
May 21, 2017: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/28528968/amylin-and-its-g-protein-coupled-receptor-a-probable-pathological-process-and-drug-target-for-alzheimer-s-disease
#7
REVIEW
Wei Qiao Qiu
G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer's disease (AD) pathogenesis. However, because GPCRs include a large family of membrane receptors, it is unclear which specific GPCR or pathway with rational ligands can become effective therapeutic targets for AD. Amylin receptor (AmR) is a GPCR that mediates several activities, such as improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reactions and potentially enhancing neural regeneration. Recent studies show that peripheral treatments with amylin or its clinical analog, pramlintide, reduced several components of AD pathology, including amyloid plaques, tauopathy, neuroinflammation and other components in the brain, corresponding with improved learning and memory in AD mouse models...
May 18, 2017: Neuroscience
https://www.readbyqxmd.com/read/28528321/omega-3-fatty-acids-lipids-and-apoe-lipidation-in-alzheimer-s-disease-a-rationale-for-multi-nutrient-dementia-prevention
#8
Marcus O Grimm, Daniel Michaelson, Tobias Hartmann
In the last decade it has become obvious that Alzheimer's disease (AD) is closely linked to changes in lipids or lipid metabolism. One of the main pathological hallmarks of AD is amyloid-β (Aβ) deposition. Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP). Interestingly, both, the APP and all APP secretases are transmembrane proteins which cleave APP close to and in the lipid bilayer. Moreover, apolipoprotein E4 (apoE4) has been identified as the most prevalent genetic risk factor for AD...
May 20, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28528185/simvastatin-ameliorate-memory-deficits-and-inflammation-in-clinical-and-mouse-model-of-alzheimer-s-disease-via-modulating-the-expression-of-mir-106b
#9
Wenzhong Huang, Zhenyu Li, Liandong Zhao, Wei Zhao
BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored. METHODS: First, we tested the effect of simvastatin on AD in clinical research...
May 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28528007/luteolin-as-a-potential-preventive-and-therapeutic-candidate-for-alzheimer-s-disease
#10
Youngjoo Kwon
Amyloid cascade hypothesis is the main theoretical framework describing the development of Alzheimer's disease (AD). However, most clinical trials of therapy targeting amyloid-β peptide (Aβ) are unsuccessful because AD is a complex disease involving many genetic and environmental factors. Among various factors, inflammation within the brain in particular has been implicated in the pathogenesis and progression of AD. Furthermore, it has been shown that systemic inflammation can initiate AD. Therefore, anti-inflammatory agents might be beneficial for prevention and/or treatment of AD...
May 17, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28527974/the-effect-of-%C3%AE-sheet-breaker-peptides-on-metal-associated-amyloid-%C3%AE-peptide-aggregation-process
#11
F Stellato, Z Fusco, R Chiaraluce, V Consalvi, S Dinarelli, E Placidi, M Petrosino, G C Rossi, V Minicozzi, S Morante
Far-UV Circular Dichroism experiments and Atomic Force Microscopy tomography are employed to assess the impact of β-sheet breakers on the Aβ1-40 peptide aggregation process in the presence of Cu(2+) or Zn(2+) transition metals. In this work we focus on two specific 5-amino acids long β-sheet breakers, namely the LPFFD Soto peptide, already known in the literature, and the LPFFN peptide recently designed and studied by our team. We provide evidence that both β-sheet breakers are effective in reducing the Aβ1-40 aggregation propensity, even in the presence of metal ions...
May 15, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28527218/the-mechanisms-of-action-of-curcumin-in%C3%A2-alzheimer-s-disease
#12
Mengxi Tang, Changiz Taghibiglou
Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant...
May 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28527217/protein-phosphorylation-is-a-key-mechanism-in-alzheimer-s-disease
#13
Joana Oliveira, Márcio Costa, Maria Soares Cachide de Almeida, Odete A B da Cruz E Silva, Ana Gabriela Henriques
Altered protein phosphorylation states of several proteins are closely associated with Alzheimer's disease (AD). Among these are the amyloid-β precursor protein (AβPP) and the tau protein. In fact, altered protein phosphorylation states already provide strong biomarkers for AD diagnosis, as is the case with hyperphosphorylated tau. It follows that modulating signaling cascades provides an attractive avenue for exploring novel therapeutic strategies. This review focuses on some of the major protein kinases and protein phosphatases relevant to AD...
May 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28526839/fluorescence-correlation-spectroscopy-reveals-a-cooperative-unfolding-of-monomeric-amyloid-%C3%AE-42-with-a-low-gibbs-free-energy
#14
Mario Schneider, Stefan Walta, Chris Cadek, Walter Richtering, Dieter Willbold
The amyloid-beta peptide (Aβ) plays a major role in the progression of Alzheimer's disease. Due to its high toxicity, the 42 amino acid long isoform Aβ42 has become of considerable interest. The Aβ42 monomer is prone to aggregation down to the nanomolar range which makes conventional structural methods such as NMR or X-ray crystallography infeasible. Conformational information, however, will be helpful to understand the different aggregation pathways reported in the literature and will allow to identify potential conditions that favour aggregation-incompetent conformations...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526436/intracranial-il-17a-overexpression-decreases-cerebral-amyloid-angiopathy-by-upregulation-of-abca1-in-an-animal-model-of-alzheimer-s-disease
#15
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...
May 17, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28521611/sgpl1-sphingosine-phosphate-lyase-1-modulates-neuronal-autophagy-via-phosphatidylethanolamine-production
#16
Daniel N Mitroi, Indulekha Karunakaran, Markus Gräler, Julie D Saba, Dan Ehninger, María Dolores Ledesma, Gerhild van Echten-Deckert
Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons. SGPL1 cleaves S1P into ethanolamine phosphate, which is directed toward the synthesis of phosphatidylethanolamine (PE) that anchors LC3-I to phagophore membranes in the form of LC3-II...
May 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28520620/-epigallocatechin-3-gallate-ameliorates-memory-impairment-and-rescues-the-abnormal-synaptic-protein-levels-in-the-frontal-cortex-and-hippocampus-in-a-mouse-model-of-alzheimer-s-disease
#17
Yufang Guo, Yan Zhao, Ying Nan, Xiang Wang, Yulong Chen, Shuang Wang
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic extract in green tea and it has attracted increasing attention for its multiple bioactive effects. However, the mechanisms by which EGCG exerts its neuroprotective actions in Alzheimer's disease (AD) are presently lacking. In the present study, a sporadic AD transgenic mouse model known as senescence-accelerated mouse prone 8 (SAMP8) was used to investigate whether oral administration of EGCG could improve recognition and memory function through reduction of amyloid β (Aβ) and tau hyperphosphorylation...
May 17, 2017: Neuroreport
https://www.readbyqxmd.com/read/28515429/endocytic-uptake-of-monomeric-amyloid-%C3%AE-peptides-is-clathrin-and-dynamin-independent-and-results-in-selective-accumulation-of-a%C3%AE-1-42-compared-to-a%C3%AE-1-40
#18
Emelie Wesén, Gavin D M Jeffries, Maria Matson Dzebo, Elin K Esbjörner
Intraneuronal accumulation of amyloid-β (Aβ) peptides represent an early pathological feature in Alzheimer's disease. We have therefore utilized flow cytometry and confocal microscopy in combination with endocytosis inhibition to explore the internalisation efficiency and uptake mechanisms of Aβ(1-40) and Aβ(1-42) monomers in cultured SH-SY5Y cells. We find that both variants are constitutively internalised via endocytosis and that their uptake is proportional to cellular endocytic rate. Moreover, SH-SY5Y cells internalise consistently twice the amount of Aβ(1-42) compared to Aβ(1-40); an imaging-based quantification showed that cells treated with 1 µM peptide for 8 h contained 800,000 peptides of Aβ(1-42) and 400,000 of Aβ(1-40)...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515043/brain-perivascular-macrophages-initiate-the-neurovascular-dysfunction-of-alzheimer-a%C3%AE-peptides
#19
Laibaik Park, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pitstick, Linda H Younkin, Steven G Younkin, Ping Zhou, Geroge A Carlson, Josef Anrather, Costantino Iadecola
Rationale: Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer's disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS)...
May 17, 2017: Circulation Research
https://www.readbyqxmd.com/read/28513756/divergent-synthesis-of-biflavonoids-yields-novel-inhibitors-of-the-aggregation-of-amyloid-%C3%AE-1-42
#20
Tze Han Sum, Tze Jing Sum, Súil Collins, Warren R J D Galloway, David G Twigg, Florian Hollfelder, David R Spring
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids...
May 17, 2017: Organic & Biomolecular Chemistry
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