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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/28810892/absence-of-cx3cr1-impairs-the-internalization-of-tau-by-microglia
#1
Marta Bolós, María Llorens-Martín, Juan Ramón Perea, Jerónimo Jurado-Arjona, Alberto Rábano, Félix Hernández, Jesús Avila
BACKGROUND: Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism. METHODS: We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1(-/-) mice)...
August 15, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28774322/tau-accumulation-in-the-retina-promotes-early-neuronal-dysfunction-and-precedes-brain-pathology-in-a-mouse-model-of-alzheimer-s-disease
#2
Marius Chiasseu, Luis Alarcon-Martinez, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Laurie Destroismaisons, Christine Vande Velde, Fany Panayi, Caroline Louis, Adriana Di Polo
BACKGROUND: Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer's disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood...
August 3, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28768549/intranasal-insulin-reverts-central-pathology-and-cognitive-impairment-in-diabetic-mother-offspring
#3
Juan Jose Ramos-Rodriguez, Daniel Sanchez-Sotano, Alberto Doblas-Marquez, Carmen Infante-Garcia, Simon Lubian-Lopez, Monica Garcia-Alloza
BACKGROUND: Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. METHODS: Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates...
August 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28768545/trem2-in-neurodegenerative-diseases
#4
REVIEW
Taylor R Jay, Victoria E von Saucken, Gary E Landreth
TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics...
August 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28743268/the-lysosomal-protein-cathepsin-l-is-a-progranulin-protease
#5
Chris W Lee, Jeannette N Stankowski, Jeannie Chew, Casey N Cook, Ying-Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok-Fai Lau, Mercedes Prudencio, Fen-Biao Gao, Matthew Bogyo, Dennis W Dickson, Leonard Petrucelli
Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments...
July 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28697798/a-proteomic-analysis-of-lrrk2-binding-partners-reveals-interactions-with-multiple-signaling-components-of-the-wnt-pcp-pathway
#6
Alena Salašová, Chika Yokota, David Potěšil, Zbyněk Zdráhal, Vítězslav Bryja, Ernest Arenas
BACKGROUND: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients...
July 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28683776/trpa1-channels-promote-astrocytic-ca-2-hyperactivity-and-synaptic-dysfunction-mediated-by-oligomeric-forms-of-amyloid-%C3%AE-peptide
#7
Anthony Bosson, Adrien Paumier, Sylvie Boisseau, Muriel Jacquier-Sarlin, Alain Buisson, Mireille Albrieux
BACKGROUND: Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease (AD). However, the key mechanisms that maintain plasticity of synapses during adulthood or initiate synapse dysfunction in AD remain unknown. Recent studies suggest that astrocytes contribute to functional changes observed during synaptic plasticity and play a major role in synaptic dysfunction but astrocytes behavior and involvement in early phases of AD remained largely undefined. METHODS: We measure astrocytic calcium activity in mouse CA1 hippocampus stratum radiatum in both the global astrocytic population and at a single cell level, focusing in the highly compartmentalized astrocytic arbor...
July 6, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28676095/toll-like-receptor-4-stimulation-with-monophosphoryl-lipid-a-ameliorates-motor-deficits-and-nigral-neurodegeneration-triggered-by-extraneuronal-%C3%AE-synucleinopathy
#8
Serena Venezia, Violetta Refolo, Alexia Polissidis, Leonidas Stefanis, Gregor K Wenning, Nadia Stefanova
BACKGROUND: Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innate immunity response. It was previously shown that TLR4 plays a role in the clearance of α-syn, suggesting that TLR4 up-regulation in microglia may be a natural mechanism to improve the clearance of α-syn...
July 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28668092/dissecting-the-role-of-non-coding-rnas-in-the-accumulation-of-amyloid-and-tau-neuropathologies-in-alzheimer-s-disease
#9
Ellis Patrick, Sathyapriya Rajagopal, Hon-Kit Andus Wong, Cristin McCabe, Jishu Xu, Anna Tang, Selina H Imboywa, Julie A Schneider, Nathalie Pochet, Anna M Krichevsky, Lori B Chibnik, David A Bennett, Philip L De Jager
BACKGROUND: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer's disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer's disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region. METHODS: We report analyses of expression profiling of miRNA (n = 700 subjects) and lincRNA (n = 540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging...
July 1, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28662669/glial-contributions-to-neurodegeneration-in-tauopathies
#10
REVIEW
Cheryl E G Leyns, David M Holtzman
Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer's disease (AD) which is the most common form of dementia...
June 29, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28633663/targeting-psychologic-stress-signaling-pathways-in-alzheimer-s-disease
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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