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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/28526038/phosphorylation-of-tau-at-y18-but-not-tau-fyn-binding-is-required-for-tau-to-modulate-nmda-receptor-dependent-excitotoxicity-in-primary-neuronal-culture
#1
Takashi Miyamoto, Liana Stein, Reuben Thomas, Biljana Djukic, Praveen Taneja, Joseph Knox, Keith Vossel, Lennart Mucke
BACKGROUND: Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear...
May 19, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28521765/inhibition-of-o-glcnacase-leads-to-elevation-of-o-glcnac-tau-and-reduction-of-tauopathy-and-cerebrospinal-fluid-tau-in-rtg4510-mice
#2
Nicholas B Hastings, Xiaohai Wang, Lixin Song, Brent D Butts, Diane Grotz, Richard Hargreaves, J Fred Hess, Kwok-Lam Karen Hong, Cathy Ruey-Ruey Huang, Lynn Hyde, Maureen Laverty, Julie Lee, Diane Levitan, Sherry X Lu, Maureen Maguire, Veeravan Mahadomrongkul, Ernest J McEachern, Xuesong Ouyang, Thomas W Rosahl, Harold Selnick, Michaela Stanton, Giuseppe Terracina, David J Vocadlo, Ganfeng Wang, Joseph L Duffy, Eric M Parker, Lili Zhang
BACKGROUND: Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models...
May 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28499404/anterograde-monosynaptic-transneuronal-tracers-derived-from-herpes-simplex-virus-1-strain-h129
#3
Wen-Bo Zeng, Hai-Fei Jiang, Ya-Dong Gang, Yi-Ge Song, Zhang-Zhou Shen, Hong Yang, Xiao Dong, Yong-Lu Tian, Rong-Jun Ni, Yaping Liu, Na Tang, Xinyan Li, Xuan Jiang, Ding Gao, Michelle Androulakis, Xiao-Bin He, Hui-Min Xia, Ying-Zi Ming, Youming Lu, Jiang-Ning Zhou, Chen Zhang, Xue-Shan Xia, Yousheng Shu, Shao-Qun Zeng, Fuqiang Xu, Fei Zhao, Min-Hua Luo
BACKGROUND: Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer. METHODS: Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing...
May 12, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28482850/mutant-tdp-43-does-not-impair-mitochondrial-bioenergetics-in-vitro-and-in-vivo
#4
Hibiki Kawamata, Pablo Peixoto, Csaba Konrad, Gloria Palomo, Kirsten Bredvik, Meri Gerges, Federica Valsecchi, Leonard Petrucelli, John M Ravits, Anatoly Starkov, Giovanni Manfredi
BACKGROUND: Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics...
May 8, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28478762/diurnal-oscillation-of-csf-a%C3%AE-and-other-ad-biomarkers
#5
Brendan P Lucey, Anne M Fagan, David M Holtzman, John C Morris, Randall J Bateman
To assess stages of Alzheimer's disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. Significant within-person variations in CSF Aβ concentrations over time found that this variation followed the sleep-wake cycle. A recent paper in Molecular Neurodegeneration reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E...
May 8, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28476168/dioxins-and-related-environmental-contaminants-increase-tdp-43-levels
#6
Peter E A Ash, Elizabeth A Stanford, Ali Al Abdulatif, Alejandra Ramirez-Cardenas, Heather I Ballance, Samantha Boudeau, Amanda Jeh, James M Murithi, Yorghos Tripodis, George J Murphy, David H Sherr, Benjamin Wolozin
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor...
May 5, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28472993/humanized-monoclonal-antibody-armanezumab-specific-to-n-terminus-of-pathological-tau-characterization-and-therapeutic-potency
#7
Michael G Agadjanyan, Karen Zagorski, Irina Petrushina, Hayk Davtyan, Konstantin Kazarian, Maxim Antonenko, Joy Davis, Charles Bon, Mathew Blurton-Jones, David H Cribbs, Anahit Ghochikyan
BACKGROUND: The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2-18 termed "phosphatase activation domain" that is normally hidden in the native protein in 'paperclip'-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau...
May 5, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28472990/downregulating-anp32a-rescues-synapse-and-memory-loss-via-chromatin-remodeling-in-alzheimer-model
#8
Gao-Shang Chai, Qiong Feng, Zhi-Hao Wang, Yu Hu, Dong-Sheng Sun, Xiao-Guang Li, Dan Ke, Hong-Lian Li, Gong-Ping Liu, Jian-Zhi Wang
BACKGROUND: The impairment of histone acetylation is causally linked to the cognitive decline in Alzheimer's disease (AD). In addition to histone acetyltransferases (HATs) and histone deacetylases (HDACs), inhibitor of acetyltransferases (INHAT) can also regulate histone acetylation. As a key component of INHAT, level of ANP32A is selectively upregulated in the brain of AD patients. Here we investigated whether downregulating ANP32A can rescue AD-like synapse and memory deficits. METHODS: RFP-labeled lentiviral ANP32A-shRNA was infused stereotaxically into the hippocampal CA3 region of the human tau transgenic mice (termed htau)...
May 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28438208/amelioration-of-amyloid-%C3%AE-induced-deficits-by-dcr3-in-an-alzheimer-s-disease-model
#9
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/28438176/the-pink1-p-i368n-mutation-affects-protein-stability-and-ubiquitin-kinase-activity
#10
Maya Ando, Fabienne C Fiesel, Roman Hudec, Thomas R Caulfield, Kotaro Ogaki, Paulina Górka-Skoczylas, Dariusz Koziorowski, Andrzej Friedman, Li Chen, Valina L Dawson, Ted M Dawson, Guojun Bu, Owen A Ross, Zbigniew K Wszolek, Wolfdieter Springer
BACKGROUND: Mutations in PINK1 and PARKIN are the most common causes of recessive early-onset Parkinson's disease (EOPD). Together, the mitochondrial ubiquitin (Ub) kinase PINK1 and the cytosolic E3 Ub ligase PARKIN direct a complex regulated, sequential mitochondrial quality control. Thereby, damaged mitochondria are identified and targeted to degradation in order to prevent their accumulation and eventually cell death. Homozygous or compound heterozygous loss of either gene function disrupts this protective pathway, though at different steps and by distinct mechanisms...
April 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28438165/microglia-derived-il-1%C3%AE-promotes-chemokine-expression-by-m%C3%A3-ller-cells-and-rpe-in-focal-retinal-degeneration
#11
Riccardo Natoli, Nilisha Fernando, Michele Madigan, Joshua A Chu-Tan, Krisztina Valter, Jan Provis, Matt Rutar
BACKGROUND: Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. METHODS: Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage...
April 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28399904/separation-of-photoreceptor-cell-compartments-in-mouse-retina-for-protein-analysis
#12
Kasey Rose, Steven T Walston, Jeannie Chen
BACKGROUND: Light exposure triggers movement of certain signaling proteins within the cellular compartments of the highly polarized rod photoreceptor cell. This redistribution of proteins between the inner and outer segment compartments affects the performance and physiology of the rod cell. In addition, newly synthesized phototransduction proteins traverse from the site of their synthesis in the inner segment, through the thin connecting cilium, to reach their destination in the outer segment...
April 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28399880/quantitative-proteomic-analysis-of-parkin-substrates-in-drosophila-neurons
#13
Aitor Martinez, Benoit Lectez, Juanma Ramirez, Oliver Popp, James D Sutherland, Sylvie Urbé, Gunnar Dittmar, Michael J Clague, Ugo Mayor
BACKGROUND: Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings...
April 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28327181/soluble-oligomeric-amyloid-%C3%AE-induces-calcium-dyshomeostasis-that-precedes-synapse-loss-in-the-living-mouse-brain
#14
Michal Arbel-Ornath, Eloise Hudry, Josiah R Boivin, Tadafumi Hashimoto, Shuko Takeda, Kishore V Kuchibhotla, Steven Hou, Carli R Lattarulo, Arianna M Belcher, Naomi Shakerdge, Pariss B Trujillo, Alona Muzikansky, Rebecca A Betensky, Bradley T Hyman, Brian J Bacskai
BACKGROUND: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer's disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. METHOD: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging...
March 21, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28320441/decreased-cortical-fadd-protein-is-associated-with-clinical-dementia-and-cognitive-decline-in-an-elderly-community-sample
#15
Alfredo Ramos-Miguel, Jesús A García-Sevilla, Alasdair M Barr, Thomas A Bayer, Peter Falkai, Sue E Leurgans, Julie A Schneider, David A Bennett, William G Honer, M Julia García-Fuster
BACKGROUND: FADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample. METHODS: FADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57)...
March 20, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28279219/tetraspanin-6-a-pivotal-protein-of-the-multiple-vesicular-body-determining-exosome-release-and-lysosomal-degradation-of-amyloid-precursor-protein-fragments
#16
Francesc X Guix, Ragna Sannerud, Fedor Berditchevski, Amaia M Arranz, Katrien Horré, An Snellinx, Amantha Thathiah, Takaomi Saido, Takashi Saito, Sundaresan Rajesh, Michael Overduin, Samir Kumar-Singh, Enrico Radaelli, Nikky Corthout, Julien Colombelli, Sébastien Tosi, Sebastian Munck, Isabel H Salas, Wim Annaert, Bart De Strooper
BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer's disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. RESULTS: Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time...
March 10, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28270179/blood-cholesterol-in-late-life-and-cognitive-decline-a-longitudinal-study-of-the-chinese-elderly
#17
Chaoran Ma, Zhaoxue Yin, Pengfei Zhu, Jiesi Luo, Xiaoming Shi, Xiang Gao
BACKGROUND: Previous studies regarding the lipid-cognition relation in older adults are limited and have generated mixed results. We thus examined whether higher blood cholesterol concentrations were associated with faster cognitive decline in a community-based longitudinal study of Chinese elderly. METHODS: The study included 1,159 Chinese adults aged over 60 years (women: 48.7%, mean age: 79.4 years), who were free of dementia, Parkinson disease and stroke at the baseline...
March 7, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28241840/increased-acetylation-of-peroxiredoxin1-by-hdac6-inhibition-leads-to-recovery-of-a%C3%AE-induced-impaired-axonal-transport
#18
Heesun Choi, Haeng Jun Kim, Jisoo Kim, Soohyun Kim, Jinhee Yang, Wonik Lee, Yeonju Park, Seung Jae Hyeon, Dong-Sup Lee, Hoon Ryu, Junho Chung, Inhee Mook-Jung
BACKGROUND: Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. METHODS AND RESULTS: Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients...
February 28, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28241839/caspase-vinyl-sulfone-small-molecule-inhibitors-prevent-axonal-degeneration-in-human-neurons-and-reverse-cognitive-impairment-in-caspase-6-overexpressing-mice
#19
Prateep Pakavathkumar, Anastasia Noël, Clotilde Lecrux, Agne Tubeleviciute-Aydin, Edith Hamel, Jan-Eric Ahlfors, Andrea C LeBlanc
BACKGROUND: The activation of the aspartate-specific cysteinyl protease, Caspase-6, is proposed as an early pathogenic event of Alzheimer disease (AD) and Huntington's disease. Caspase-6 inhibitors could be useful against these neurodegenerative diseases but most Caspase-6 inhibitors have been exclusively studied in vitro or show acute liver toxicity in humans. Here, we assessed vinyl sulfone small molecule peptide caspase inhibitors for potential use in vivo. METHODS: The IC50 of NWL vinyl sulfone small molecule caspase inhibitors were determined on Caspase-1 to 10, and Caspase-6-transfected human colon carcinoma HCT116 cells...
February 28, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28235423/spatiotemporal-progression-of-ubiquitin-proteasome-system-inhibition-after-status-epilepticus-suggests-protective-adaptation-against-hippocampal-injury
#20
Tobias Engel, Jaime Martinez-Villarreal, Christine Henke, Eva M Jimenez-Mateos, Amaya Sanz-Rodriguez, Mariana Alves, Yasmina Hernandez-Santana, Gary P Brennan, Aidan Kenny, Aoife Campbell, Jose J Lucas, David C Henshall
BACKGROUND: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases...
February 24, 2017: Molecular Neurodegeneration
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