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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/28633663/targeting-psychologic-stress-signaling-pathways-in-alzheimer-s-disease
#1
REVIEW
Hunter S Futch, Cara L Croft, Van Q Truong, Eric G Krause, Todd E Golde
Alzheimer's Disease (AD) is the most prevalent progressive neurodegenerative disease; to date, no AD therapy has proven effective in delaying or preventing the disease course. In the search for novel therapeutic targets in AD, it has been shown that increased chronic psychologic stress is associated with AD risk. Subsequently, biologic pathways underlying psychologic stress have been identified and shown to be able to exacerbate AD relevant pathologies. In this review, we summarize the literature relevant to the association between psychologic stress and AD, focusing on studies investigating the effects of stress paradigms on transgenic mouse models of Amyloid-β (Aβ) and tau pathologies...
June 21, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28619096/presenilins-regulate-synaptic-plasticity-and-mitochondrial-calcium-homeostasis-in-the-hippocampal-mossy-fiber-pathway
#2
Sang Hun Lee, David Lutz, Mohanad Mossalam, Vadim Y Bolshakov, Michael Frotscher, Jie Shen
BACKGROUND: Presenilins play a major role in the pathogenesis of Alzheimer's disease, in which the hippocampus is particularly vulnerable. Previous studies of Presenilin function in the synapse, however, focused exclusively on the hippocampal Schaffer collateral (SC) pathway. Whether Presenilins play similar or distinct roles in other hippocampal synapses is unknown. METHODS: To investigate the role of Presenilins at mossy fiber (MF) synapses we performed field and whole-cell electrophysiological recordings and Ca(2+) imaging using acute hippocampal slices of postnatal forebrain-restricted Presenilin conditional double knockout (PS cDKO) and control mice at 2 months of age...
June 15, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28606182/microglia-limit-the-expansion-of-%C3%AE-amyloid-plaques-in-a-mouse-model-of-alzheimer-s-disease
#3
Ruohe Zhao, Wanling Hu, Julia Tsai, Wei Li, Wen-Biao Gan
BACKGROUND: Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) plaques in the brain of Alzheimer's disease (AD) are surrounded by microglia, but whether and how microglia affect the formation and maintenance of plaques remains controversial. METHODS: We depleted microglia by injecting diphtheria toxin (DT) in CX 3 CR1 (CreER/+) :R26 (DTR/+) (CX 3 CR1-iDTR) mice crossed with APPswe/PSEN1dE9 (APP/PS1) mice. Intravital time-lapse imaging was performed to examine changes in the number and size of Congo Red-labeled amyloid plaques over 1-2 weeks...
June 12, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28606110/a-c9orf72-bac-mouse-model-recapitulates-key-epigenetic-perturbations-of-als-ftd
#4
Rustam Esanov, Gabriela Toro Cabrera, Nadja S Andrade, Tania F Gendron, Robert H Brown, Michael Benatar, Claes Wahlestedt, Christian Mueller, Zane Zeier
BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal and progressive neurodegenerative disorder with identified genetic causes representing a significant minority of all cases. A GGGGCC hexanucleotide repeat expansion (HRE) mutation within the C9ORF72 gene has recently been identified as the most frequent known cause of ALS. The expansion leads to partial heterochromatinization of the locus, yet mutant RNAs and dipeptide repeat proteins (DPRs) are still produced in sufficient quantities to confer neurotoxicity...
June 12, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28592329/autoimmune-antibody-decline-in-parkinson-s-disease-and-multiple-system-atrophy-a-step-towards-immunotherapeutic-strategies
#5
Tomasz Brudek, Kristian Winge, Jonas Folke, Søren Christensen, Karina Fog, Bente Pakkenberg, Lars Østergaard Pedersen
BACKGROUND: Parkinson's' disease (PD) and Multiple System Atrophy (MSA) are progressive brain disorders characterized by intracellular accumulations of α-synuclein and nerve cell loss in specific brain areas. This loss causes problems with movement, balance and/or autonomic functions. Naturally occurring autoantibodies (NAbs) play potentially an important role in clearing or/and blocking circulating pathological proteins. Little is known about the functional properties of anti-α-synuclein NAbs in PD and MSA, and there have been opposing reports regarding their plasma concentrations in these disorders...
June 7, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28592304/post-translational-changes-to-%C3%AE-synuclein-control-iron-and-dopamine-trafficking-a-concept-for-neuron-vulnerability-in-parkinson-s-disease
#6
REVIEW
James A Duce, Bruce X Wong, Hannah Durham, Jean-Christophe Devedjian, David P Smith, David Devos
Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking...
June 7, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28552073/intrastriatal-injection-of-%C3%AE-synuclein-can-lead-to-widespread-synucleinopathy-independent-of-neuroanatomic-connectivity
#7
Zachary A Sorrentino, Mieu M T Brooks, Vincent Hudson, Nicola J Rutherford, Todd E Golde, Benoit I Giasson, Paramita Chakrabarty
BACKGROUND: Prionoid transmission of α-synuclein (αSyn) aggregates along neuroanatomically connected projections is posited to underlie disease progression in α-synucleinopathies. Here, we specifically wanted to study whether this prionoid progression occurs via direct inter-neuronal transfer and, if so, would intrastriatal injection of αSyn aggregates lead to nigral degeneration. METHODS: To test prionoid transmission of αSyn aggregates along the nigro-striatal pathway, we injected amyloidogenic αSyn aggregates into two different regions of the striatum of adult human wild type αSyn transgenic mice (Line M20) or non-transgenic (NTG) mice and aged for 4 months...
May 29, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28549481/late-onset-alzheimer-s-disease-genetics-implicates-microglial-pathways-in-disease-risk
#8
REVIEW
Anastasia G Efthymiou, Alison M Goate
Alzheimer's disease (AD) is a highly heritable complex disease with no current effective prevention or treatment. The majority of drugs developed for AD focus on the amyloid cascade hypothesis, which implicates Aß plaques as a causal factor in the disease. However, it is possible that other underexplored disease-associated pathways may be more fruitful targets for drug development. Findings from gene network analyses implicate immune networks as being enriched in AD; many of the genes in these networks fall within genomic regions that contain common and rare variants that are associated with increased risk of developing AD...
May 26, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28545479/endoplasmic-reticulum-stress-and-inflammation-in-the-central-nervous-system
#9
REVIEW
Neil T Sprenkle, Savannah G Sims, Cristina L Sánchez, Gordon P Meares
Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu...
May 25, 2017: Molecular Neurodegeneration
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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