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https://www.readbyqxmd.com/read/28728117/alzheimer-s-disease-markers-in-the-aged-sheep-ovis-aries
#1
Suzanne J Reid, Natasha E Mckean, Kristen Henty, Erik Portelius, Kaj Blennow, Skye R Rudiger, C Simon Bawden, Renee R Handley, Paul J Verma, Richard L M Faull, Henry J Waldvogel, Henrik Zetterberg, Russell G Snell
This study reports the identification and characterization of markers of Alzheimer's disease (AD) in aged sheep (Ovis aries) as a preliminary step toward making a genetically modified large animal model of AD. Importantly, the sequences of key proteins involved in AD pathogenesis are highly conserved between sheep and human. The processing of the amyloid-β (Aβ) protein is conserved between sheep and human, and sheep Aβ1-42/Aβ1-40 ratios in cerebrospinal fluid (CSF) are also very similar to human. In addition, total tau and neurofilament light levels in CSF are comparable with those found in human...
June 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28728108/new-tacrine-dimers-with-antioxidant-linkers-as-dual-drugs-anti-alzheimer-s-and-antiproliferative-agents
#2
Jesús M Roldán-Peña, Daniel Alejandre-Ramos, Óscar López, Inés Maya, Irene Lagunes, José M Padrón, Luis Emiliano Peña-Altamira, Manuela Bartolini, Barbara Monti, Maria L Bolognesi, José G Fernández-Bolaños
We have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives...
June 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28728105/discovery-of-imidazopyridines-containing-isoindoline-1-3-dione-framework-as-a-new-class-of-bace1-inhibitors-design-synthesis-and-sar-analysis
#3
Sara Azimi, Afsaneh Zonouzi, Omidreza Firuzi, Aida Iraji, Mina Saeedi, Mohammad Mahdavi, Najmeh Edraki
Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-β. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-β aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke-Blackburn-Bienaymé three-component reaction of heteroaromatic amidines, aldehydes and isocyanides...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28728104/design-synthesis-and-evaluation-of-coumarin-pargyline-hybrids-as-novel-dual-inhibitors-of-monoamine-oxidases-and-amyloid-%C3%AE-aggregation-for-the-treatment-of-alzheimer-s-disease
#4
Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Fan Li, Jin Wang, Jia-Jia Wu, Xiao-Bing Wang, Ling-Yi Kong
A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test...
July 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28727426/fully-atomistic-a%C3%AE-40-and-a%C3%AE-42-oligomers-in-water-observation-of-pore-like-conformations
#5
Matthew John Voelker, Bogdan Barz, Brigita Urbanc
Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers...
July 20, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28726777/humanin-g-hng-protects-age-related-macular-degeneration-amd-transmitochondrial-arpe-19-cybrids-from-mitochondrial-and-cellular-damage
#6
Sonali Nashine, Pinchas Cohen, Marilyn Chwa, Stephanie Lu, Anthony B Nesburn, Baruch D Kuppermann, M Cristina Kenney
Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated...
July 20, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28726016/amyloid-%C3%AE-derived-from-the-brain-of-the-alzheimer-s-disease-transgenic-mouse-is-resistant-to-proteolytic-digestion-due-to-its-conformation
#7
Baian Chen, Jing Zhang, Shubo Wang, Wen Wang, Zitong Yao, Quan Sun, Yi Wu, Jing Lu
The main pathological feature of Alzheimer's disease (AD) is the formation of abundant amyloid-β (Aβ) plaques in the human brain. Studies have reported that Aβ from the AD brain is resistant to proteolytic digestion, which may explain why Aβ cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Aβ derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Aβ peptide, whose amino acid sequence was identical to that of AD mouse-derived Aβ but whose conformation was different (i...
July 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28725210/multicenter-analytical-validation-of-a%C3%AE-40-immunoassays
#8
Linda J C van Waalwijk van Doorn, Luka Kulic, Marleen J A Koel-Simmelink, H Bea Kuiperij, Alexandra A M Versleijen, Hanne Struyfs, Harry A M Twaalfhoven, Anthony Fourier, Sebastiaan Engelborghs, Armand Perret-Liaudet, Sylvain Lehmann, Marcel M Verbeek, Eugeen J M Vanmechelen, Charlotte E Teunissen
BACKGROUND: Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-β peptide 1-42 and 1-40 (Aβ42/Aβ40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aβ40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28722194/effects-of-cholesterol-transport-inhibitor-u18666a-on-app-metabolism-in-rat-primary-astrocytes
#9
Hongyan Yang, Yanlin Wang, Satyabrata Kar
Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol-which increase the risk of developing AD-can influence Aβ production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A-a class II amphiphile that triggers redistribution of cholesterol within the endosomal-lysosomal (EL) system-on APP levels and metabolism in rat primary cultured astrocytes...
July 19, 2017: Glia
https://www.readbyqxmd.com/read/28721727/synthesis-of-intricate-fused-n-heterocycles-via-ring-rearrangement-metathesis
#10
Sambasivarao Kotha, Rama Gunta
Herein, a facile synthesis of intricate fused N-heterocycles has been disclosed by employing C-H activation and ring-rearrangement metathesis/enyne ring-rearrangement metathesis as key steps. Interestingly, some of these N-heterocyclic products possess the tricyclic core of epimeloscine, deoxycalyciphylline B, daphlongamine H, isodaphlongamine H and a bioactive alkaloid, annotinolide A, which shows anti-aggregation activity against amyloid-β (Aβ)1-42 peptide aggregation. Moreover, various starting materials required in this protocol are easily assembled via C-X bond annulation of 2-bromo-N-protected aniline with norbornadiene or directing group-assisted ruthenium-catalyzed C-H activation of N-methoxybenzamide...
July 19, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28720896/nanoscale-control-of-amyloid-self-assembly-using-protein-phase-transfer-by-host-guest-chemistry
#11
Tae Su Choi, Hong Hee Lee, Young Ho Ko, Kwang Seob Jeong, Kimoon Kim, Hugh I Kim
Amyloid fibrils have recently been highlighted for their diverse applications as functional nanomaterials in modern chemistry. However, tight control to obtain a targeted fibril length with low heterogeneity has not been achieved because of the complicated nature of amyloid fibrillation. Herein, we demonstrate that fibril assemblies can be homogeneously manipulated with desired lengths from ~40 nm to ~10 μm by a phase transfer of amyloid proteins based on host-guest chemistry. We suggest that host-guest interactions with cucurbit[6]uril induce a phase transfer of amyloid proteins (human insulin, human islet amyloid polypeptide, hen egg lysozyme, and amyloid-β 1-40 & 1-42) from the soluble state to insoluble state when the amount of cucurbit[6]uril exceeds its solubility limit in solution...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720893/nanoplasmonic-fiber-tip-probe-detects-significant-reduction-of-intracellular-alzheimer-s-disease-related-oligomers-by-curcumin
#12
Feng Liang, Yu Wan, Diane Schaak, Joseph Ward, Xunuo Shen, Rudolph E Tanzi, Can Zhang, Qimin Quan
Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer's disease (AD). In particular, intracellular amyloid-β accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720101/drug-candidates-in-clinical-trials-for-alzheimer-s-disease
#13
REVIEW
Shih-Ya Hung, Wen-Mei Fu
Alzheimer's disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation...
July 19, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28719344/protective-effect-of-edaravone-against-a%C3%AE-25-35-induced-mitochondrial-oxidative-damage-in-sh-sy5y-cells
#14
G-L Zhang, L Zhang, Y-Y Guo, Z-L Ma, H-Y Wang, T Li, J Liu, Y Du, L Yao, T-T Li, J-M Du
Amyloid-β (Aβ)-induced oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). Recent studies show that Aβ accumulation may lead to mitochondrial oxidative damage. In the present study, we investigated the protective effect of edaravone on mitochondrial damage in SH-SY5Y cells treated with Aβ25-35. SH-SY5Y cells were pre-treated with 20, 40 or 80 μM edaravone before treatment with 25 μM Aβ25-35. After 24h cell culture, cellular apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), ATP levels and mitochondrial morphology were evaluated...
May 20, 2017: Cellular and Molecular Biology
https://www.readbyqxmd.com/read/28718623/a-multimodal-spectroscopic-imaging-method-to-characterize-the-metal-and-macromolecular-content-of-proteinaceous-aggregates-amyloid-plaques
#15
Kelly L Summers, Nicholas Fimognari, Ashley Hollings, Mitchell Kiernan, Virginie Lam, Rebecca J Tidy, David Paterson, Mark J Tobin, Ryu Takechi, Graham N George, Ingrid J Pickering, John C Mamo, Hugh H Harris, Mark J Hackett
Alzheimer's disease (AD) is a major international health and economic concern. A key pathological feature of AD is so-called "amyloid-β-plaques", or "Aβ-plaques", which are deposits of aggregated protein, enriched with the Aβ fragment of amyloid precursor protein. Despite their name, the deposits are not pure Aβ and have a heterogeneous, chemically complex composition that can include multiple proteins, lipids, and metal ions (Fe, Cu, or Zn). Despite extensive research, it is still uncertain whether Aβ-plaques are a cause or a consequence of AD pathology...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28717091/thrombolysis-related-multiple-lobar-hemorrhaging-in-cerebral-amyloid-angiopathy-with-extensive-strictly-lobar-cerebral-microbleeding
#16
Makoto Eriguchi, Yusuke Yakushiji, Jun Tanaka, Masashi Nishihara, Hideo Hara
A hemi-paralyzed 86-year-old man was diagnosed with ischemic stroke and underwent thrombolysis. Pre-thrombolysis brain magnetic resonance imaging revealed extensive strictly lobar cerebral microbleeding (CMB). Post-thrombolytic computed tomography revealed asymptomatic multiple intracerebral hemorrhaging (ICH). His age, CMB topography, and decreased cerebral spinal fluid amyloid-β 40 and 42 levels were compatible with a diagnosis of cerebral amyloid angiopathy (CAA). There is no consensus on the safety of thrombolysis for acute stroke patients with CAA...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28715708/the-evaluation-of-brain-perfusion-spect-using-an-easy-z-score-imaging-system-in-the-mild-cognitive-impairment-subjects-with-brain-amyloid-%C3%AE-deposition
#17
Makoto Takemaru, Noriyuki Kimura, Yoshitake Abe, Megumi Goto, Etsuro Matsubara
OBJECTIVE: The analysis of (99)mTc-ECD single-photon emission computed tomography (SPECT) images using the easy Z-score imaging system (eZIS) program is useful for the diagnosis of early AD in daily medical practice. However, it remains unclear whether eZIS analysis can identify the amnestic mild cognitive impairment (MCI) subjects with brain amyloid-β deposition. The aim of this study was to evaluate the usefulness of an eZIS analysis for predicting amnestic MCI subjects with brain amyloid β deposition...
July 5, 2017: Clinical Neurology and Neurosurgery
https://www.readbyqxmd.com/read/28715661/cognitive-decline-and-brain-amyloid-%C3%AE-accumulation-across-3-years-in-adults-with-down-syndrome
#18
Sigan L Hartley, Benjamin L Handen, Darlynne Devenny, Iulia Mihaila, Regina Hardison, Patrick J Lao, William E Klunk, Peter Bulova, Sterling C Johnson, Bradley T Christian
Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum...
June 2, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28714389/a-peptide-based-pro-drug-ameliorates-amyloid-%C3%AE-induced-neuronal-apoptosis-in-in-vitro-sh-sy5y-cells
#19
Sourav Kumar, Ashim Paul, Sourav Kalita, Awanish Kumar, Saurabh Srivastav, Somoday Hazra, Anup Kumar Ghosh, Bhubaneswar Mandal, Amal Chandra Mondal
BACKGROUND: Alzheimer's disease (AD), a common protein misfolding neurodegenerative disorder, is one of the most common forms of dementia. Amyloid precursor protein (APP) derived amyloid-β (Aβ) proteins accumulated into interneuronal spaces and plays a crucial role in the disease progression and its pathology. The aggregated Aβ exerts its neurotoxic effects by inducing apoptosis and oxidative damage in neuronal cells. OBJECTIVES: We have investigated the effects of a synthesized Pro-Drug peptide (PDp) on Aβ1-40 induced cytotoxicity in human neuroblastoma SH-SY5Y cells, represents one of the most effective strategies in combating human AD...
July 13, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28714019/salidroside-protects-pc12-cells-from-a%C3%AE-1%C3%A2-40%C3%A2-induced-cytotoxicity-by-regulating-the-nicotinamide-phosphoribosyltransferase-signaling-pathway
#20
Xujiao Huang, Sanli Xing, Chuan Chen, Zhihua Yu, Jiulin Chen
Alzheimer's disease (AD) is the most common type of senile dementia, which often develops in elderly or presenile individuals. As one of the pathological features of AD, amyloid β‑protein (Aβ) causes energy dysmetabolism, thereby inducing cellular damage and apoptosis. Salidroside is the main active component of the traditional Chinese medicine Rhodiola. Previous studies have demonstrated that salidroside exerts a regulatory role in energy metabolism. However, the role and the mechanism of action of salidroside in AD remain unclear...
July 5, 2017: Molecular Medicine Reports
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