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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/29859124/protective-paraspeckle-hyper-assembly-downstream-of-tdp-43-loss-of-function-in-amyotrophic-lateral-sclerosis
#1
Tatyana A Shelkovnikova, Michail S Kukharsky, Haiyan An, Pasquale Dimasi, Svetlana Alexeeva, Osman Shabir, Paul R Heath, Vladimir L Buchman
BACKGROUND: Paraspeckles are subnuclear bodies assembled on a long non-coding RNA (lncRNA) NEAT1. Their enhanced formation in spinal neurons of sporadic amyotrophic lateral sclerosis (ALS) patients has been reported but underlying mechanisms are unknown. The majority of ALS cases are characterized by TDP-43 proteinopathy. In current study we aimed to establish whether and how TDP-43 pathology may augment paraspeckle assembly. METHODS: Paraspeckle formation in human samples was analysed by RNA-FISH and laser capture microdissection followed by qRT-PCR...
June 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29859094/the-trem2-r47h-variant-confers-loss-of-function-like-phenotypes-in-alzheimer-s-disease
#2
Paul J Cheng-Hathaway, Erin G Reed-Geaghan, Taylor R Jay, Brad T Casali, Shane M Bemiller, Shweta S Puntambekar, Victoria E von Saucken, Roxanne Y Williams, J Colleen Karlo, Miguel Moutinho, Guixiang Xu, Richard M Ransohoff, Bruce T Lamb, Gary E Landreth
BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2...
June 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29793507/targeting-energy-metabolism-via-the-mitochondrial-pyruvate-carrier-as-a-novel-approach-to-attenuate-neurodegeneration
#3
REVIEW
Emmanuel Quansah, Wouter Peelaerts, J William Langston, David K Simon, Jerry Colca, Patrik Brundin
Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria...
May 24, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29788997/2d-versus-3d-human-induced-pluripotent-stem-cell-derived-cultures-for-neurodegenerative-disease-modelling
#4
REVIEW
Eduarda G Z Centeno, Helena Cimarosti, Angela Bithell
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results...
May 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#5
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29783994/large-scale-transcriptomic-analysis-reveals-that-pridopidine-reverses-aberrant-gene-expression-and-activates-neuroprotective-pathways-in-the-yac128-hd-mouse
#6
Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-Chong, Marta Garcia-Miralles, Liang Juin Tan, Michael E Burczynski, Ben Zeskind, Daphna Laifenfeld, Mahmoud Pouladi, Michal Geva, Iris Grossman, Michael R Hayden
BACKGROUND: Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29783988/tolerogenic-bone-marrow-derived-dendritic-cells-induce-neuroprotective-regulatory-t-cells-in-a-model-of-parkinson-s-disease
#7
Charles R Schutt, Howard E Gendelman, R Lee Mosley
BACKGROUND: Administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases regulatory T cell (Treg) number and function with control of neuroinflammation and neuronal protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Recently, we demonstrated in an early phase 1 clinical trial that GM-CSF also improves motor skills in PD patients. However, the mechanisms of Treg induction and its effects on neuroprotective responses remain unknown...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29776378/differential-induction-of-mutant-sod1-misfolding-and-aggregation-by-tau-and-%C3%AE-synuclein-pathology
#8
Michael C Pace, Guilian Xu, Susan Fromholt, John Howard, Benoit I Giasson, Jada Lewis, David R Borchelt
BACKGROUND: Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS: Mice expressing high levels of mutant forms of tau and α-synuclein (αSyn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation...
May 18, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29764453/ampa-ergic-regulation-of-amyloid-%C3%AE-levels-in-an-alzheimer-s-disease-mouse-model
#9
Jane C Hettinger, Hyo Lee, Guojun Bu, David M Holtzman, John R Cirrito
BACKGROUND: Extracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms...
May 15, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29751824/inoculation-of-%C3%AE-synuclein-preformed-fibrils-into-the-mouse-gastrointestinal-tract-induces-lewy-body-like-aggregates-in-the-brainstem-via-the-vagus-nerve
#10
Norihito Uemura, Hisashi Yagi, Maiko T Uemura, Yusuke Hatanaka, Hodaka Yamakado, Ryosuke Takahashi
BACKGROUND: Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction...
May 11, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29716629/vibrational-spectroscopy-a-promising-approach-to-discriminate-neurodegenerative-disorders
#11
LETTER
Maria Paraskevaidi, Pierre L Martin-Hirsch, Francis L Martin
Neurodegenerative diseases are a growing burden in modern society, thus crucially calling for the development of accurate diagnostic strategies. These diseases are currently incurable, a fact which has been attributed to their late diagnosis, after brain damage has already become widespread. An earlier and improved diagnosis is necessary for the enrolment of patients into clinical trials and can pave the way for the development of therapeutic tactics. Novel analytical techniques, such as mass spectrometry and vibrational spectroscopy, have been able to successfully detect and characterise neurodegenerative disorders...
May 2, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29661219/modulation-of-gsk-3-provides-cellular-and-functional-neuroprotection-in-the-rd10-mouse-model-of-retinitis-pigmentosa
#12
Alonso Sánchez-Cruz, Beatriz Villarejo-Zori, Miguel Marchena, Josefa Zaldivar-Díez, Valle Palomo, Carmen Gil, Ignacio Lizasoain, Pedro de la Villa, Ana Martínez, Enrique J de la Rosa, Catalina Hernández-Sánchez
BACKGROUND: Retinitis pigmentosa (RP) is a group of hereditary retinal neurodegenerative conditions characterized by primary dysfunction and death of photoreceptor cells, resulting in visual loss and, eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of RP, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy. METHODS: Using the Pde6b rd10/rd10 mouse model of RP, we investigated the effects of daily intraperitoneal administration of VP3...
April 16, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29625583/structural-and-mechanistic-aspects-influencing-the-adam10-mediated-shedding-of-the-prion-protein
#13
Luise Linsenmeier, Behnam Mohammadi, Sebastian Wetzel, Berta Puig, Walker S Jackson, Alexander Hartmann, Keiji Uchiyama, Suehiro Sakaguchi, Kristina Endres, Jörg Tatzelt, Paul Saftig, Markus Glatzel, Hermann C Altmeppen
Background: Proteolytic processing of the prion protein (PrP<superscript>C</superscript>) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrP<superscript>C</superscript> into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer’s and prion disease...
April 6, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29618365/apolipoprotein-e4-impairs-spontaneous-blood-brain-barrier-repair-following-traumatic-brain-injury
#14
Bevan S Main, Sonia Villapol, Stephanie S Sloley, David J Barton, Maia Parsadanian, Chinyere Agbaegbu, Kathryn Stefos, Mondona S McCann, Patricia M Washington, Olga C Rodriguez, Mark P Burns
BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated...
April 4, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29615095/loss-of-xbp1-accelerates-age-related-decline-in-retinal-function-and-neurodegeneration
#15
Todd McLaughlin, Marek Falkowski, Jae Whan Park, Stephen Keegan, Michael Elliott, Joshua J Wang, Sarah X Zhang
BACKGROUND: Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses...
April 4, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29587871/amyloid-beta-modulates-microglial-responses-by-binding-to-the-triggering-receptor-expressed-on-myeloid-cells-2-trem2
#16
Li Zhong, Zongqi Wang, Daxin Wang, Zhe Wang, Yuka A Martens, Linbei Wu, Ying Xu, Kai Wang, Jianguo Li, Ruizhi Huang, Dan Can, Huaxi Xu, Guojun Bu, Xiao-Fen Chen
BACKGROUND: TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer's disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined. METHODS: Potential binding of oligomeric amyloid-β 1-42 (oAβ1-42 ) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays...
March 27, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29566703/cognitive-impairment-in-metabolically-obese-normal-weight-rats-identification-of-early-biomarkers-in-peripheral-blood-mononuclear-cells
#17
Margalida Cifre, Andreu Palou, Paula Oliver
BACKGROUND: Metabolically-obese, normal-weight (MONW) individuals are not obese in terms of weight and height but have a number of obesity-related features (e.g. greater visceral adiposity, insulin resistance, and increased risk of cardiovascular disease). The MONW phenotype is related to the intake of unbalanced diets, such as those rich in fat. Increasing evidence shows a relationship between high-fat diet consumption and mild cognitive impairment and dementia. Thus, MONW individuals could be at a greater risk of cognitive dysfunction...
March 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29544548/tau-oligomers-mediate-%C3%AE-synuclein-toxicity-and-can-be-targeted-by-immunotherapy
#18
Julia E Gerson, Kathleen M Farmer, Natalie Henson, Diana L Castillo-Carranza, Mariana Carretero Murillo, Urmi Sengupta, Alan Barrett, Rakez Kayed
BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target...
March 15, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29514656/targeting-hif1a-rescues-cone-degeneration-and-prevents-subretinal-neovascularization-in-a-model-of-chronic-hypoxia
#19
Maya Barben, Christian Schori, Marijana Samardzija, Christian Grimm
BACKGROUND: Degeneration of cone photoreceptors leads to loss of vision in patients suffering from age-related macular degeneration (AMD) and other cone dystrophies. Evidence, such as choroidal ischemia and decreased choroidal blood flow, implicates reduced tissue oxygenation in AMD pathology and suggests a role of the cellular response to hypoxia in disease onset and progression. Such a chronic hypoxic situation may promote several cellular responses including stabilization of hypoxia-inducible factors (HIFs)...
March 7, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29490706/early-long-term-administration-of-the-csf1r-inhibitor-plx3397-ablates-microglia-and-reduces-accumulation-of-intraneuronal-amyloid-neuritic-plaque-deposition-and-pre-fibrillar-oligomers-in-5xfad-mouse-model-of-alzheimer-s-disease
#20
Justyna Sosna, Stephan Philipp, Ricardo Albay, Jorge Mauricio Reyes-Ruiz, David Baglietto-Vargas, Frank M LaFerla, Charles G Glabe
BACKGROUND: Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both...
March 1, 2018: Molecular Neurodegeneration
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