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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/28327181/soluble-oligomeric-amyloid-%C3%AE-induces-calcium-dyshomeostasis-that-precedes-synapse-loss-in-the-living-mouse-brain
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28143566/apoe-genotype-differentially-modulates-effects-of-anti-a%C3%AE-passive-immunization-in-app-transgenic-mice
#16
Joanna E Pankiewicz, Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M Sullivan, David M Holtzman, Martin J Sadowski
BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: APPSW/PS1dE9 (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds...
January 31, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28122627/therapeutic-potential-of-autophagy-enhancing-agents-in-parkinson-s-disease
#17
REVIEW
Tim E Moors, Jeroen J M Hoozemans, Angela Ingrassia, Tommaso Beccari, Lucilla Parnetti, Marie-Christine Chartier-Harlin, Wilma D J van de Berg
Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson's Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn)...
January 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28118852/the-sh-sy5y-cell-line-in-parkinson-s-disease-research-a-systematic-review
#18
REVIEW
Helena Xicoy, Bé Wieringa, Gerard J M Martens
Parkinson's disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage...
January 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28103901/pathogenic-lrrk2-variants-are-gain-of-function-mutations-that-enhance-lrrk2-mediated-repression-of-%C3%AE-catenin-signaling
#19
Daniel C Berwick, Behzad Javaheri, Andrea Wetzel, Mark Hopkinson, Jonathon Nixon-Abell, Simone Grannò, Andrew A Pitsillides, Kirsten Harvey
BACKGROUND: LRRK2 mutations and risk variants increase susceptibility to inherited and idiopathic Parkinson's disease, while recent studies have identified potential protective variants. This, and the fact that LRRK2 mutation carriers develop symptoms and brain pathology almost indistinguishable from idiopathic Parkinson's disease, has led to enormous interest in this protein. LRRK2 has been implicated in a range of cellular events, but key among them is canonical Wnt signalling, which results in increased levels of transcriptionally active β-catenin...
January 19, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28103900/gde2-is-essential-for-neuronal-survival-in-the-postnatal-mammalian-spinal-cord
#20
Clinton Cave, Sungjin Park, Marianeli Rodriguez, Mai Nakamura, Ahmet Hoke, Mikhail Pletnikov, Shanthini Sockanathan
BACKGROUND: Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2's roles beyond embryonic neurogenesis have yet to be defined. METHOD: Using a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2 (-/-) mouse for evidence of degenerative neuropathology...
January 19, 2017: Molecular Neurodegeneration
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