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Amyloid-β

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https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#1
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28922156/soluble-oligomers-require-a-ganglioside-to-trigger-neuronal-calcium-overload
#2
Roberta Cascella, Elisa Evangelisti, Alessandra Bigi, Matteo Becatti, Claudia Fiorillo, Massimo Stefani, Fabrizio Chiti, Cristina Cecchi
An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28922155/phospho-tau-accumulation-and-structural-alterations-of-the-golgi-apparatus-of-cortical-pyramidal-neurons-in-the-p301s%C3%A2-tauopathy-mouse-model
#3
Alejandro Antón-Fernández, Jesús Merchán-Rubira, Jesús Avila, Félix Hernández, Javier DeFelipe, Alberto Muñoz
The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients...
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/28919280/soluble-gamma-secretase-modulators-attenuate-alzheimer-s-%C3%AE-amyloid-pathology-and-induce-conformational-changes-in-presenilin-1
#5
Frank Raven, Joseph F Ward, Katarzyna M Zoltowska, Yu Wan, Enjana Bylykbashi, Sean J Miller, Xunuo Shen, Se Hoon Choi, Kevin D Rynearson, Oksana Berezovska, Steven L Wagner, Rudolph E Tanzi, Can Zhang
A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations...
September 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28919235/alzheimer-s-disease-like-paired-helical-filament-assembly-from-truncated-tau-protein-is-independent-of-disulphide-cross-linking
#6
Youssra K Al-Hilaly, Saskia J Pollack, Devkee Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise C Serpell
Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28918941/modulation-of-%C3%AE-and-%C3%AE-secretases-as-early-prevention-against-alzheimer-s-disease
#7
REVIEW
Iryna Voytyuk, Bart De Strooper, Lucía Chávez-Gutiérrez
The genetic evidence implicating amyloid-β in the initial stage of Alzheimer's disease is unequivocal. However, the long biochemical and cellular prodromal phases of the disease suggest that dementia is the result of a series of molecular and cellular cascades whose nature and connections remain unknown. Therefore, it is unlikely that treatments directed at amyloid-β will have major clinical effects in the later stages of the disease. We discuss the two major candidate therapeutic targets to lower amyloid-β in a preventive mode, i...
August 10, 2017: Biological Psychiatry
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
#8
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/28916413/emerging-structural-understanding-of-amyloid-fibrils-by-solid-state-nmr
#9
REVIEW
Beat H Meier, Roland Riek, Anja Böckmann
Amyloid structures at atomic resolution have remained elusive mainly because of their extensive polymorphism and because their polymeric properties have hampered structural studies by classical approaches. Progress in sample preparation, as well as solid-state NMR methods, recently enabled the determination of high-resolution 3D structures of fibrils such as the amyloid-β fibril, which is involved in Alzheimer's disease. Notably, the simultaneous but independent structure determination of Aβ1-42, a peptide that forms fibrillar deposits in the brain of Alzheimer patients, by two independent laboratories, which yielded virtually identical results, has highlighted how structures can be obtained that allow further functional investigation...
September 12, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28914525/two-distinct-polymorphic-folding-states-of-self-assembly-of-the-non-amyloid-%C3%AE-component-differ-in-the-arrangement-of-the-residues
#10
Maya Pollock-Gagolashvili, Yifat Miller
Parkinson's disease is a degenerative disorder of the central nerves system. It is characterized by presence of Lew bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the "non-amyloid β component" (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains are crucial in order to understand the molecular mechanisms of AS aggregation...
September 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28912710/key-aging-associated-alterations-in-primary-microglia-response-to-beta-amyloid-stimulation
#11
Cláudia Caldeira, Carolina Cunha, Ana R Vaz, Ana S Falcão, Andreia Barateiro, Elsa Seixas, Adelaide Fernandes, Dora Brites
Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28912445/cofilin-mediated-neuronal-apoptosis-via-p53-translocation-and-pld1-regulation
#12
Tian Liu, Fang Wang, Patrick LePochat, Jung-A A Woo, Mohammed Zaheen Bukhari, Kyung Woo Hong, Courtney Trotter, David E Kang
Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer's disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28910862/effects-of-newly-synthesized-recombinant-human-amyloid-%C3%AE-complexes-and-poly-amyloid-%C3%AE-fibers-on-cell-apoptosis-and-cognitive-decline
#13
Soojin Park, Jae-Won Huh, Taekil Eom, Naeun Na, Youngjeon Lee, Ju-Sung Kim, Sun-Uk Kim, Insop Shim, Sang-Rae Lee, Ekyune Kim
The main pathological hallmark of Alzheimer's disease is the deposition of amyloid-β peptide (Aβ) in the brain. Aβ has been widely used to mimic several aspects of Alzheimer's disease. However, several characteristics of amyloid-induced Alzheimer's disease pathology are not well established, especially in mice. The present study aimed to develop a new Alzheimer's disease model by investigating how amyloid beta can be effectively aggregated using prokaryotes and eukaryotes. To express the Aβ42 complex in HEK293 cells, we cloned the Aβ42 region repeatedly and incorporated the resulting construct into a eukaryotic expression vector...
September 15, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28910107/perturbation-of-the-f19-l34-contact-in-amyloid-ss-1-40-fibrils-induces-only-local-structural-changes-but-abolishes-cytotoxicity
#14
Felix Hoffmann, Juliane Adler, Bappaditya Chandra, Kaustubh R Mote, Gül Bekcioglu-Neff, Daniel Sebastiani, Daniel Huster
We explored structural details of fibrils formed by a mutated amyloid β (Aβ(1-40) peptide carrying a Phe19 to Lys19 mutation, which was shown to completely abolish the toxicity of the molecule. Computer models suggest that the positively charged Lys19 side-chain is expelled from the hydrophobic fibril interior upon fibrillation. This can be accommodated by either a 180° flip of the entire lower β-strand (model M1) or local perturbations of the secondary structure in the direct vicinity of the mutated site (model M2)...
September 14, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28906375/correlations-between-clinical-characteristics-and-neuroimaging-in-chinese-patients-with-subtypes-of-frontotemporal-lobe-degeneration
#15
Zhihong Shi, Shuai Liu, Ying Wang, Shuling Liu, Tong Han, Li Cai, Yuying Zhou, Shuo Gao, Yong Ji
The aim of the study was to obtain an overview of the clinical and neuroimaging features of Chinese patients with subtypes of frontotemporal lobe degeneration (FTLD).We evaluated the demographic features, clinical presentation, and lobe atrophy depicted by magnetic resonance imaging (MRI) in 133 patients with FTLD. Two positron emission tomography (PET) scans were performed at baseline: [C]Pittsburgh compound B PET to assess amyloid-β plaque load and [F]fluorodeoxyglucose (FDG) PET to assess glucose metabolism...
September 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28902714/altered-subcellular-localization-of-fragile-x-mental-retardation-signaling-partners-and-targets-in-superior-frontal-cortex-of-individuals-with-schizophrenia
#16
S Hossein Fatemi, Timothy D Folsom, Paul D Thuras
Schizophrenia is a severe, debilitating, neurodevelopmental disorder that affects 1% of the world's population. Recent findings from our laboratory have identified reduced levels of fragile X mental retardation protein (FMRP) and several downstream FMRP targets in superior frontal cortex of individuals with schizophrenia. We hypothesized that altered subcellular expression of FMRP and its signaling partners may explain these changes. In the current study we employed subcellular fractionation and western blotting to determine levels of FMRP, phosphorylated-FMRP as well as selected signaling partners [protein phosphatase 2A catalytic subunit (PP2AC), p70 S6 kinase (p70 S6K), and amyloid-β A4 precursor protein (APP)] in the total homogenate, nuclear, and rough endoplasmic reticulum fractions in superior frontal cortex of individuals with schizophrenia versus controls (N=12/group)...
September 11, 2017: Neuroreport
https://www.readbyqxmd.com/read/28902142/blood-brain-barrier-dysfunction-and-the-pathogenesis-of-alzheimer-s-disease
#17
REVIEW
Yu Yamazaki, Takahisa Kanekiyo
Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). While amyloid-β (Aβ) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist...
September 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28900141/dianxianning-improved-amyloid-%C3%AE-induced-pathological-characteristics-partially-through-daf-2-daf-16-insulin-like-pathway-in-transgenic-c-elegans
#18
Dejuan Zhi, Dong Wang, Wenqi Yang, Ziyun Duan, Shuqian Zhu, Juan Dong, Na Wang, Ningbo Wang, Dongqing Fei, Zhanxin Zhang, Xin Wang, Meizhu Wang, Hongyu Li
Dianxianning (DXN) is a traditional Chinese formula, and has been approved in China for treating epilepsy since 1996. Here anti-Alzheimer's disease activity of DXN has been reported. DXN improved AD-like symptoms of paralysis and 5-HT sensitivity of transgenic Aβ1-42 C. elegans. In worms, DXN significantly increased Aβ monomers and decreased the toxic Aβ oligomers, thus reducing Aβ toxicity. DXN significantly suppressed the expression of hsp-16.2 induced by juglone, and up-regulated sod-3 expression. These results indicated that DXN increased stress resistance and protected C...
September 12, 2017: Scientific Reports
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
#19
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/28899019/cerebral-quantitative-susceptibility-mapping-predicts-amyloid-%C3%AE-related-cognitive-decline
#20
Scott Ayton, Amir Fazlollahi, Pierrick Bourgeat, Parnesh Raniga, Amanda Ng, Yen Ying Lim, Ibrahima Diouf, Shawna Farquharson, Jurgen Fripp, David Ames, James Doecke, Patricia Desmond, Roger Ordidge, Colin L Masters, Christopher C Rowe, Paul Maruff, Victor L Villemagne, Olivier Salvado, Ashley I Bush
See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL)...
August 1, 2017: Brain: a Journal of Neurology
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