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https://www.readbyqxmd.com/read/28445751/curcumin-dictates-divergent-fates-for-the-central-salt-bridges-in-amyloid-%C3%AE-40-and-amyloid-%C3%AE-42
#1
Bappaditya Chandra, Venus Singh Mithu, Debanjan Bhowmik, Anand Kant Das, Bankanidhi Sahoo, Sudipta Maiti, Perunthiruthy K Madhu
There are three specific regions in the Amyloid beta (Aβ) peptide sequence where variations cause enhanced toxicity in Alzheimer's disease: the N-terminus, the central salt bridge, and the C-terminus. Here, we investigate if there is a close conformational connection between these three regions, which may suggest a concerted mechanism of toxicity. We measure the effects of Zn(2+) and curcumin on Aβ40, and compare these with their previously reported effects on Aβ42. Aβ42 and Aβ40 differ only near the C-terminus, where curcumin interacts, while Zn(2+) interacts near the N-terminus...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28442538/peripheral-tumor-necrosis-factor-alpha-tnf-%C3%AE-modulates-amyloid-pathology-by-regulating-blood-derived-immune-cells-and-glial-response-in-the-brain-of-ad-tnf-transgenic-mice
#2
Evi Paouri, Ourania Tzara, Georgia-Ioanna Kartalou, Sofia Zenelak, Spiros Georgopoulos
Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the central nervous system can provide potential therapeutic targets. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear...
April 25, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28442392/4-chlorodiazepam-is-neuroprotective-against-amyloid-beta-in-organotypic-hippocampal-cultures
#3
B D Arbo, J B Hoppe, K Rodrigues, L M Garcia-Segura, C G Salbego, M F Ribeiro
The translocator protein (TSPO) is an outer mitochondrial membrane protein involved in the transport of cholesterol into the mitochondria, which is the first step for the synthesis of steroid hormones, as well as in the regulation of mitochondrial permeability transition pore opening and apoptosis. Studies have shown that the activation of TSPO may promote neuroprotective actions in experimental models of neurodegeneration and brain injury. In a previous study, our group showed that 4'-chlorodiazepam (4'-CD), a TSPO ligand, was neuroprotective against amyloid-beta (Aβ) in SHSY-5Y neuroblastoma cells...
April 22, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28441890/rosuvastatin-ameliorates-cognitive-impairment-in-rats-fed-with-high-salt-and-cholesterol-diet-via-inhibiting-acetylcholinesterase-activity-and-amyloid-beta-peptide-aggregation
#4
I Husain, M Akhtar, M Zainul Abdin, M Islamuddin, M Shaharyar, A K Najmi
Amyloid beta (Aβ) peptide aggregation and cholinergic neurodegeneration are involved in the development of cognitive impairment. Therefore, in this article, we examined rosuvastatin (RSV), an oral hypolipidemic drug, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for the treatment of cognitive impairment. Molecular docking study was done to examine the affinity of RSV with Aβ1-42 and AChE in silico. We also employed neurobehavioral activity tests, biochemical estimation, and histopathology to study the anti-Aβ1-42 aggregation capability of RSV in vivo...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/28438208/amelioration-of-amyloid-%C3%AE-induced-deficits-by-dcr3-in-an-alzheimer-s-disease-model
#5
Yi-Ling Liu, Wei-Ting Chen, Yu-Yi Lin, Po-Hung Lu, Shie-Liang Hsieh, Irene Han-Juo Cheng
BACKGROUND: Microglia mediate amyloid-beta peptide (Aβ)-induced neuroinflammation, which is one of the key events in the pathogenesis of Alzheimer's disease (AD). Decoy receptor 3 (DcR3)/TNFRSF6B is a pleiotropic immunomodulator that promotes macrophage differentiation toward the M2 anti-inflammatory phenotype. Based on its role as an immunosupressor, we examined whether DcR3 could alleviate neuroinflammation and AD-like deficits in the central nervous system. METHOD: We crossed human APP transgenic mice (line J20) with human DcR3 transgenic mice to generate wild-type, APP, DcR3, and APP/DcR3 mice for pathological analysis...
April 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28437250/ionizing-radiation-reduces-adam10-expression-in-brain-microvascular-endothelial-cells-undergoing-stress-induced-senescence
#6
Lucinda S McRobb, Matthew J McKay, Jennifer R Gamble, Michael Grace, Vaughan Moutrie, Estevam D Santos, Vivienne S Lee, Zhenjun Zhao, Mark P Molloy, Marcus A Stoodley
Cellular senescence is associated with aging and is considered a potential contributor to age-associated neurodegenerative disease. Exposure to ionizing radiation increases the risk of developing premature neurovascular degeneration and dementia but also induces premature senescence. As cells of the cerebrovascular endothelium are particularly susceptible to radiation and play an important role in brain homeostasis, we investigated radiation-induced senescence in brain microvascular endothelial cells (EC). Using biotinylation to label surface proteins, streptavidin enrichment and proteomic analysis, we analyzed the surface proteome of stress-induced senescent EC in culture...
April 17, 2017: Aging
https://www.readbyqxmd.com/read/28435985/elucidating-the-a%C3%AE-42-anti-aggregation-mechanism-of-action-of-tramiprosate-in-alzheimer-s-disease-integrating-molecular-analytical-methods-pharmacokinetic-and-clinical-data
#7
Petr Kocis, Martin Tolar, Jeremy Yu, William Sinko, Soumya Ray, Kaj Blennow, Howard Fillit, John A Hey
BACKGROUND: Amyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer's disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease...
April 24, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28434642/-late-life-depression-or-prodromal-alzheimer-s-disease-which-tools-for-the-differential-diagnosis
#8
A-I Gasser, V Salamin, S Zumbach
INTRODUCTION: Depression and Alzheimer's disease are both very frequent in elderly people. Cognitive deficits are the hallmark of Alzheimer's disease, but they are also common in depressed elderly people who often present cognitive deficits such as memory, attention and executive function problems. On the other hand, people with early Alzheimer's disease demonstrate emotional and behavioral disorders generally encountered in depression such as loss of energy, apathy, mood disorder, and irritability...
April 20, 2017: L'Encéphale
https://www.readbyqxmd.com/read/28430602/fluoxetine-attenuates-the-impairment-of-spatial-learning-ability-and-prevents-neuron-loss-in-middle-aged-appswe-psen1de9-double-transgenic-alzheimer-s-disease-mice
#9
Jing Ma, Yuan Gao, Lin Jiang, Feng-Lei Chao, Wei Huang, Chun-Ni Zhou, Wei Tang, Lei Zhang, Chun-Xia Huang, Yi Zhang, Yan-Min Luo, Qian Xiao, Hua-Rong Yu, Rong Jiang, Yong Tang
Selective serotonin reuptake inhibitors (SSRIs) have been reported to increase cognitive performance in some clinical studies of Alzheimer's disease (AD). However, there is a lack of evidence supporting the efficacy of SSRIs as cognition enhancers in AD, and the role of SSRIs as a treatment for AD remains largely unclear. Here, we characterized the impact of fluoxetine (FLX), a well-known SSRI, on neurons in the dentate gyrus (DG) and in CA1 and CA3 of the hippocampus of middle-aged (16 to 17 months old) APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429668/the-role-of-mitochondria-associated-reactive-oxygen-species-in-the-amyloid-%C3%AE-induced-production-of-angiogenic-factors-by-arpe-19-cells
#10
L Wu, X Tan, L Liang, H Yu, C Wang, D Zhang, A Kijlstra, P Yang
OBJECTIVE: This study aimed to investigate the mechanisms whereby Amyloid-beta (Aβ) induces the production of angiogenic factors by a human retinal pigment epithelial cell line (ARPE-19) cells. METHODS: ARPE-19 cells obtained from the American Type Culture Collection (ATCC) were utilized in this study. The expression level of vascular endothelial growth factor (VEGF), Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and complement activation fragments C3a and C5a were measured by Real-time quantitative PCR (RT-PCR) and Enzyme-linked immunosorbent assay (ELISA)...
March 31, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28428554/network-assisted-analysis-of-gwas-data-identifies-a-functionally-relevant-gene-module-for-childhood-onset-asthma
#11
Y Liu, M Brossard, C Sarnowski, A Vaysse, M Moffatt, P Margaritte-Jeannin, F Llinares-López, M H Dizier, M Lathrop, W Cookson, E Bouzigon, F Demenais
The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level P-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28427941/elongation-affinity-activation-barrier-and-stability-of-a%C3%AE-42-oligomers-fibrils-in-physiological-saline
#12
Roberto A Rodriguez, Liao Y Chen, Germán Plascencia-Villa, George Perry
Amyloid-beta (Aβ) peptides, Aβ40 and the more neurotoxic Aβ42, have been the subject of many research efforts for Alzheimer's disease. In two recent independent investigations, the atomistic structure of Aβ42 fibril has been clearly established in the S-shaped conformation consisting of three β-sheets stabilized by salt bridges formed between the Lys28 sidechain and the C-terminus of Ala42. This structure distinctively differs from the long-known structure of Aβ40 in the β-hairpin shaped conformation consisting of two β-sheets...
April 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28427866/effect-of-amyloid-%C3%AE-25-35-in-hyperglycemic-and-hyperinsulinemic-rats-effects-on-phosphorylation-and-o-glcnacylation-of-tau-protein
#13
Liliana Lozano, Jorge Guevara, Tony Lefebvre, Ivan Ramos-Martinez, Daniel Limón, Alfonso Díaz, Eduarda Cerón, Edgar Zenteno
Aggregation of the amyloid beta (Aβ) peptide and hyperphosphorylation of tau protein, which are markers of Alzheimer's disease (AD), have been reported also in diabetes mellitus (DM). One regulator of tau phosphorylation is O-GlcNAcylation, whereas for hyperphosphorylation it could be GSK3beta, which is activated in hyperglycemic conditions. With this in mind, both O-GlcNAcylation and phosphorylation of tau protein were evaluated in the brain of rats with streptozotocin (STZ)-induced hyperglycemia and hyperinsulinemia and treated with the Aß25-35 peptide in the hippocampal region CA1...
April 6, 2017: Neuropeptides
https://www.readbyqxmd.com/read/28421738/targeting-the-nrf2-amyloid-beta-liaison-in-alzheimer-s-disease-a-rational-approach
#14
Elena Simoni, Melania M Serafini, Roberta Caporaso, Chiara Marchetti, Marco Racchi, Anna Minarini, Manuela Bartolini, Cristina Lanni, Michela Rosini
Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-β peptide (Aβ) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aβ and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aβ-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation...
April 25, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28420704/influence-of-hdl-particles-on-cell-cholesterol-efflux-under-various-pathological-conditions
#15
Bela F Asztalos, Katalin V Horvath, Michael Mehan, Yuya Yokota, Ernst J Schaefer
It has been reported that low cell-cholesterol efflux capacity (CEC) of HDL is an independent risk factor for CVD. To better understand CEC regulation, we measured ABCA1- and SR-BI-dependent cell-cholesterol efflux, HDL anti-oxidative capacity, HDL particles, lipids, and inflammatory- and oxidative-stress markers in 122 subjects with elevated plasma levels of TG, serum amyloid A (SAA), fibrinogen, myeloperoxidase (MPO), or β-sitosterol and in 146 controls. In controls, there were strong positive correlations between ABCA1-dependent cholesterol efflux and small prebeta-1 concentrations (R2=0...
April 18, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28417423/evaluation-of-the-expression-of-amyloid-precursor-protein-and-the-ratio-of-secreted-amyloid-beta-42-to-amyloid-beta-40-in-sh-sy5y-cells-stably-transfected-with-wild-type-single-mutant-and-double-mutant-forms-of-the-app-gene-for-the-study-of-alzheimer-s-disease
#16
Aslina Pahrudin Arrozi, Siti Nur Syazwani Shukri, Wan Zurinah Wan Ngah, Yasmin Anum Mohd Yusof, Mohd Hanafi Ahmad Damanhuri, Suzana Makpol
Neuroblastoma cell lines such as SH-SY5Y are the most frequently utilized models in neurodegenerative research, and their use has advanced the understanding of the pathology of neurodegeneration over the past few decades. In Alzheimer's disease (AD), several pathogenic mutations have been described, all of which cause elevated levels of pathological hallmarks such as amyloid-beta (Aβ). Although the genetics of Alzheimer's disease is well known, familial AD only accounts for a small number of cases in the population, with the rest being sporadic AD, which contains no known mutations...
April 17, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28416393/tdp-43-expression-influences-amyloid%C3%AE-plaque-deposition-and-tau-aggregation
#17
Stephani A Davis, Kok Ann Gan, James A Dowell, Nigel J Cairns, Michael A Gitcho
Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9)...
April 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28414234/impact-of-mutations-at-c-terminus-on-structures-and-dynamics-of-a%C3%AE-40-and-a%C3%AE-42-molecular-simulation-study
#18
Nguyen Hoang Linh, Thu Thi Minh Tran, Ly Anh Tu, Chin-Kun Hu, Mai Suan Li
Alzheimer's disease is presumably caused by formation of intracellular plaques of amyloid beta (Aβ) peptides inside neurons. The most abundant Aβ forms are Aβ40 and Aβ42 composing, respectively, of 40 and 42 residues. Recent experiments showed that triple Gly33Val-Val36Pro-Gly38Val (VPV) mutation makes Aβ42 become super-Aβ42 with elevated aggregation rates and toxicity. Upon VPV mutation oligomerization pathways of Aβ40 become similar to those of Aβ42 wild type. It was hypothesized that the super behavior of Aβ42 occurs due to enhanced content of the β-turn and β-hairpin, centered at residues 36-37 , while the similarity of oligomerization pathways of Aβ40-VPV and Aβ42-WT comes from increased β-turn population...
April 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28413992/screening-and-elucidation-of-selected-natural-compounds-for-anti-alzheimer-s-potential-targeting-bace-1-enzyme-a-case-computational-study
#19
Syed Sayeed Ahmad, Salman Akhtar, Syed Mohd Danish Rizvi, Mohammad A Kamal, Usman Sayeed, Mohd Kalim A Khan, Mohd Haris Siddiqui, Jamal M Arif
BACKGROUND: The present study clarifies the molecular interactions of human BACE1 with novel natural ligands and also with the well-known ligand 2, 2, 4-trihydroxychalcone and Galangin for comparison. OBJECTIVE: The study of enzyme- ligands interaction is interest, description of ligands binding to the active site of target molecule could be beneficial to better understanding the mechanism of the ligand on the target molecule. METHOD: Lipinski rule of five, and docking study was performed between ligands and enzyme using 'Autodock4...
April 14, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28413178/synthesized-a%C3%AE-42-caused-intracellular-oxidative-damage-leading-to-cell-death-via-lysosome-rupture
#20
Yuki Oku, Kazuma Murakami, Kazuhiro Irie, Jun Hoseki, Yasuyoshi Sakai
Neuronal cellular accumulation of amyloid beta peptide (Aβ) has been implicated in the pathogenesis of Alzheimer’s disease (AD). Intracellular accumulation of Aβ42, a toxic form of Aβ, was observed as an early event in AD patients. However, its contribution and the cellular mechanism of cell death remained unclear. We herein revealed the mechanism by which Aβ42 incorporated into cells leads to cell death by using chemically synthesized Aβ42 variants. The Aβ42 variant Aβ42 (E22P) which has an increased tendency to oligomerize, accumulated in lysosomes at an earlier stage than wild-type Aβ42, leading to higher ROS production and lysosomal membrane oxidation, and resulting in cell death...
April 12, 2017: Cell Structure and Function
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