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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/28438208/amelioration-of-amyloid-%C3%AE-induced-deficits-by-dcr3-in-an-alzheimer-s-disease-model
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28231842/tissue-type-plasminogen-activator-exerts-egf-like-chemokinetic-effects-on-oligodendrocytes-in-white-matter-re-myelination
#13
Camille Leonetti, Richard Macrez, Mathilde Pruvost, Yannick Hommet, Jérémie Bronsard, Antoine Fournier, Maxime Perrigault, Isabel Machin, Denis Vivien, Diego Clemente, Fernando De Castro, Eric Maubert, Fabian Docagne
BACKGROUND: The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons...
February 23, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28219449/ex-vivo-18-o-labeling-mass-spectrometry-identifies-a-peripheral-amyloid-%C3%AE-clearance-pathway
#14
Erik Portelius, Niklas Mattsson, Josef Pannee, Henrik Zetterberg, Magnus Gisslén, Hugo Vanderstichele, Eleni Gkanatsiou, Gabriela A N Crespi, Michael W Parker, Luke A Miles, Johan Gobom, Kaj Blennow
BACKGROUND: Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer's disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis...
February 20, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28219440/tau-pet-imaging-present-and-future-directions
#15
REVIEW
Laure Saint-Aubert, Laetitia Lemoine, Konstantinos Chiotis, Antoine Leuzy, Elena Rodriguez-Vieitez, Agneta Nordberg
Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3...
February 20, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28196514/defining-the-contribution-of-neuroinflammation-to-parkinson-s-disease-in-humanized-immune-system-mice
#16
Gunjan Dhawan Manocha, Angela Marie Floden, Kendra Lynn Puig, Kumi Nagamoto-Combs, Clemens R Scherzer, Colin Kelly Combs
BACKGROUND: Reactive microglia have been associated with the histological changes that occur in Parkinson's disease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson's disease have not been fully defined...
February 14, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28193238/transient-ikk2-activation-in-astrocytes-initiates-selective-non-cell-autonomous-neurodegeneration
#17
Michael Lattke, Stephanie N Reichel, Alexander Magnutzki, Alireza Abaei, Volker Rasche, Paul Walther, Dinis P Calado, Boris Ferger, Thomas Wirth, Bernd Baumann
BACKGROUND: Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking...
February 13, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28193235/dynamic-presenilin-1-and-synaptotagmin-1-interaction-modulates-exocytosis-and-amyloid-%C3%AE-production
#18
Katarzyna Marta Zoltowska, Masato Maesako, Iryna Lushnikova, Shuko Takeda, Laura J Keller, Galina Skibo, Bradley T Hyman, Oksana Berezovska
BACKGROUND: Alzheimer's disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction...
February 13, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28173832/gene-environment-interaction-between-lead-and-apolipoprotein-e4-causes-cognitive-behavior-deficits-in-mice
#19
Anna K Engstrom, Jessica M Snyder, Nobuyo Maeda, Zhengui Xia
BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory loss. Environmental factors and gene-environment interactions (GXE) may increase AD risk, accelerate cognitive decline, and impair learning and memory. However, there is currently little direct evidence supporting this hypothesis. METHODS: In this study, we assessed for a GXE between lead and ApoE4 on cognitive behavior using transgenic knock-in (KI) mice that express the human Apolipoprotein E4 allele (ApoE4-KI) or Apolipoprotein E3 allele (ApoE3-KI)...
February 7, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28153034/tdp-43-cryptic-exons-are-highly-variable-between-cell-types
#20
Yun Ha Jeong, Jonathan P Ling, Sophie Z Lin, Aneesh N Donde, Kerstin E Braunstein, Elisa Majounie, Bryan J Traynor, Katherine D LaClair, Thomas E Lloyd, Philip C Wong
BACKGROUND: TDP-43 proteinopathy is a prominent pathological feature that occurs in a number of human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myositis (IBM). Our recent finding that TDP-43 represses nonconserved cryptic exons led us to ask whether cell type-specific cryptic exons could exist to impact unique molecular pathways in brain or muscle. METHODS: In the present work, we investigated TDP-43's function in various mouse tissues to model disease pathogenesis...
February 2, 2017: Molecular Neurodegeneration
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