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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
#1
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/28917837/memantine-inhibits-%C3%AE-amyloid-aggregation-and-disassembles-preformed-%C3%AE-amyloid-aggregates
#2
Kaori Ito, Mitsuhiro Makino, Keiko Okado, Taisuke Tomita
Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble β-amyloid (Aβ) and soluble Aβ oligomers in animal models of AD. The mechanisms by which memantine reduces Aβ levels in the brain were evaluated by determining the effect of memantine on Aβ aggregation using thioflavin T and transmission electron microscopy...
September 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28916269/the-sterile-controversy-on-the-amyloid-cascade-hypothesis
#3
Marco Canevelli, Giuseppe Bruno, Matteo Cesari
In these last years, several phase III randomized controlled trials testing promising candidates sharing Aβ depots as target of their action have failed, despite showing some reductions of the brain Aβ charge. The announcements of the negative results have heated the discussion in the field and divided the scientific community between the defenders versus the opponents of the Aβ theory. In the present article, we discuss the limits of these drastic, opposite positions and we propose a novel approach to Alzheimer's disease (AD)...
September 12, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28915354/rose-essential-oil-delayed-ad-like-symptoms-by-skn-1-pathway-in-c-elegans
#4
Shuqian Zhu, Hong-Yu Li, Juan Dong, Wenqi Yang, Ting Liu, Yu Wang, Xin Wang, Meizhu Wang, Dejuan Zhi
There are no effective medications for delaying the progress of Alzheimer's disease (AD), the most common neurodegenerative disease in the world. In this study, our results with C. elegans showed that rose essential oil (REO) significantly inhibited AD-like symptoms of worm paralysis and hypersensivity to exogenous 5-HT in a dose-dependent manner. Its main components of β-citronellol and geraniol acted less effectively than the oil itself. REO significantly suppressed Aβ deposits and reduced the Aβ oligomers to alleviate the toxicity induced by Aβ over-expression...
September 15, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28913897/studying-the-progression-of-amyloid-pathology-and-its-therapy-using-translational-longitudinal-model-of-accumulation-and-distribution-of-amyloid-beta
#5
Tatiana Karelina, O Demin, Oleg Demin, Sridhar Duvvuri, Timothy Nicholas
Long term effects of amyloid targeted therapy can be studied using a mechanistic translational model of Aβ distribution and aggregation calibrated on published data in mouse and human species. AD pathology is modelled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human...
September 15, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28913661/discovery-of-non-peptidic-small-molecule-inhibitors-of-cyclophilin-d-as-neuroprotective-agents-in-a%C3%AE-induced-mitochondrial-dysfunction
#6
Insun Park, Ashwini M Londhe, Ji Woong Lim, Beoung-Geon Park, Seo Yun Jung, Jae Yeol Lee, Sang Min Lim, Kyoung Tai No, Jiyoun Lee, Ae Nim Pae
Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to β amyloid (Aβ) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD)...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28912896/investigation-of-the-safety-of-focused-ultrasound-induced-blood-brain-barrier-opening-in-a-natural-canine-model-of-aging
#7
Meaghan Anne O'Reilly, Ryan Matthew Jones, Edward Barrett, Anthony Schwab, Elizabeth Head, Kullervo Hynynen
Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits...
2017: Theranostics
https://www.readbyqxmd.com/read/28912710/key-aging-associated-alterations-in-primary-microglia-response-to-beta-amyloid-stimulation
#8
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
#9
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/28912154/inhibition-of-p25-cdk5-attenuates-tauopathy-in-mouse-and-ipsc-models-of-frontotemporal-dementia
#10
Jinsoo Seo, Oleg Kritskiy, L Ashley Watson, Scarlett J Barker, Dilip Dey, Waseem K Raja, Yuan-Ta Lin, Tak Ko, Sukhee Cho, Jay Penney, M Catarina Silva, Steven D Sheridan, Diane Lucente, James F Gusella, Bradford C Dickerson, Stephen J Haggarty, Li-Huei Tsai
Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders including Alzheimer's disease (AD). Previously, we showed that replacing endogenous p35 with the non-cleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial AD mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28911966/fluoxetine-administration-during-adolescence-attenuates-cognitive-and-synaptic-deficits-in-adult-3%C3%A3-tgad-mice
#11
Dong-Sheng Sun, Li-Feng Gao, Li Jin, Hao Wu, Qun Wang, You Zhou, Shuhao Fan, Xia Jiang, Dan Ke, Hao Lei, Jian-Zhi Wang, Gong-Ping Liu
Fluoxetine (FLX) has broad neurobiological functions and neuroprotective effects; however, the preventive effects of FLX on cognitive impairments in Alzheimer's disease (AD) have not been reported. Here, we studied whether adolescent administration of fluoxetine can prevent memory deficits in AD transgenic mice that harbour PS1m146v, APPswe and TauP301L mutations (3 × TgAD). FLX was applied through peritoneal injection to the mice at postnatal day 35 (p35) for 15 consecutive days, and the effects of FLX were observed at 6-month...
September 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28911813/functional-dynamics-in-cyclic-nucleotide-signaling-and-amyloid-inhibition
#12
REVIEW
Bryan VanSchouwen, Rashik Ahmed, Julijana Milojevic, Giuseppe Melacini
It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation...
September 11, 2017: Biochimica et Biophysica Acta
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/28910180/nrf2-mediated-ho-1-induction-and-antineuroinflammatory-activities-of-halleridone
#14
Ji Yeon Seo, Euisun Pyo, Junsoo Park, Jong-Sang Kim, Sang Hyun Sung, Won Keun Oh
Nuclear factor E2-related factor 2 (Nrf2) is the master regulator of antioxidant enzymes and is known to act on the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. Few studies have examined the bioactivity of halleridone. Herein, we investigated whether halleridone, which was isolated from the stems of the plant Cornus walteri, could regulate Nrf2-mediated heme oxygenase (HO)-1 expression and prevent intramicroglial inflammation induced by amyloid beta (Aβ)1-42 overexpression...
September 14, 2017: Journal of Medicinal Food
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
#15
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/28910085/cholesterol-changes-the-mechanism-of-a%C3%AE-peptide-binding-to-the-dmpc-bilayer
#16
Christopher Lockhart, Dmitri K Klimov
Using isobaric-isothermal all-atom replica-exchange molecular dynamics (REMD) simulations, we investigated the equilibrium binding of Abeta10-40 monomers to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer containing cholesterol. Our previous REMD simulations, which studied binding of the same peptide to the cholesterol-free DMPC bilayer, served as a control, against which we measured the impact of cholesterol. Our findings are as follows. First, addition of cholesterol to the DMPC bilayer partially expels the Abeta peptide from the hydrophobic core and promotes its binding to bilayer polar headgroups...
September 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28906103/resolving-the-atomistic-modes-of-anle138b-inhibitory-action-on-peptide-oligomer-formation
#17
Dirk Matthes, Vytautas Gapsys, Christian Griesinger, Bert L de Groot
The di-phenyl-pyrazole compound anle138b is a known inhibitor of oligomeric aggregate formation in vitro and in vivo. Therefore, anle138b is considered a promising drug candidate to beneficially interfere with neurodegenerative processes causing devastating pathologies in humans. The atomistic details of the aggregation inhibition mechanism, however, are to date unknown since the ensemble of small nonfibrillar aggregates is structurally heterogeneous and inaccessible to direct structural characterization. Here, we set out to elucidate anle138b's mode of action using all-atom molecular dynamics simulations on the multi-microsecond timescale...
September 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28904096/ripk1-mediates-a-disease-associated-microglial-response-in-alzheimer-s-disease
#18
Dimitry Ofengeim, Sonia Mazzitelli, Yasushi Ito, Judy Park DeWitt, Lauren Mifflin, Chengyu Zou, Sudeshna Das, Xian Adiconis, Hongbo Chen, Hong Zhu, Michelle A Kelliher, Joshua Z Levin, Junying Yuan
Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro...
September 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28902142/blood-brain-barrier-dysfunction-and-the-pathogenesis-of-alzheimer-s-disease
#19
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/28900376/physical-activity-and-beta-amyloid-pathology-in-alzheimer-s-disease-a-sound-mind-in-a-sound-body
#20
REVIEW
Khadije Ebrahimi, Alireza Majdi, Behrouz Baghaiee, Seyed Hojjat Hosseini, Saeed Sadigh-Eteghad
Alzheimer's disease (AD) is the most common type of dementia worldwide. Since curative treatment has not been established for AD yet and due to heavy financial and psychological costs of patients' care, special attention has been paid to preventive interventions such as physical activity. Evidence shows that physical activity has protective effects on cognitive function and memory in AD patients. Several pathologic factors are involved in AD-associated cognitive impairment some of which are preventable by physical activity...
2017: EXCLI journal
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