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Molecular Neurodegeneration

Harun Najib Noristani, Jean Charles Sabourin, Hassan Boukhaddaoui, Emilie Chan-Seng, Yannick Nicolas Gerber, Florence Evelyne Perrin
BACKGROUND: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. METHODS: We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses...
October 6, 2016: Molecular Neurodegeneration
Martina Pigoni, Johanna Wanngren, Peer-Hendrik Kuhn, Kathryn M Munro, Jenny M Gunnersen, Hiroshi Takeshima, Regina Feederle, Iryna Voytyuk, Bart De Strooper, Mikail D Levasseur, Brian J Hrupka, Stephan A Müller, Stefan F Lichtenthaler
BACKGROUND: The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer's disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L...
October 5, 2016: Molecular Neurodegeneration
Aitana Sogorb-Esteve, María-Salud García-Ayllón, Juan Fortea, Raquel Sánchez-Valle, Alberto Lleó, José-Luis Molinuevo, Javier Sáez-Valero
BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer's disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers. METHODS: Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes...
September 29, 2016: Molecular Neurodegeneration
Claudia Cicognola, Davide Chiasserini, Paolo Eusebi, Ulf Andreasson, Hugo Vanderstichele, Henrik Zetterberg, Lucilla Parnetti, Kaj Blennow
BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have gained increasing importance in the diagnostic work-up of Alzheimer's disease (AD). The core CSF biomarkers related to AD pathology (Aβ42, t-tau and p-tau) are currently used in CSF diagnostics, while candidate markers of amyloid metabolism (Aβ38, Aβ40, sAPPα, sAPPβ), synaptic loss (neurogranin), neuroinflammation (YKL-40), neuronal damage (VILIP-1) and genetic risk (apolipoprotein E) are undergoing evaluation. Diurnal fluctuation in the concentration of CSF biomarkers has been reported and may represent a preanalytical confounding factor in the laboratory diagnosis of AD...
2016: Molecular Neurodegeneration
Carmen Agustín-Pavón, Michal Mielcarek, Mireia Garriga-Canut, Mark Isalan
BACKGROUND: Synthetic zinc finger (ZF) proteins can be targeted to desired DNA sequences and are useful tools for gene therapy. We recently developed a ZF transcription repressor (ZF-KOX1) able to bind to expanded DNA CAG-repeats in the huntingtin (HTT) gene, which are found in Huntington's disease (HD). This ZF acutely repressed mutant HTT expression in a mouse model of HD and delayed neurological symptoms (clasping) for up to 3 weeks. In the present work, we sought to develop a long-term single-injection gene therapy approach in the brain...
2016: Molecular Neurodegeneration
Alina Ilie, Andy Y L Gao, Jonathan Reid, Annie Boucher, Cassandra McEwan, Hervé Barrière, Gergely L Lukacs, R Anne McKinney, John Orlowski
BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability...
2016: Molecular Neurodegeneration
Erin E Congdon, Yan Lin, Hameetha B Rajamohamedsait, Dov B Shamir, Senthilkumar Krishnaswamy, Wajitha J Rajamohamedsait, Suhail Rasool, Veronica Gonzalez, Josien Levenga, Jiaping Gu, Charles Hoeffer, Einar M Sigurdsson
BACKGROUND: A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures...
2016: Molecular Neurodegeneration
Natalie Landeck, Hélène Hall, Mustafa T Ardah, Nour K Majbour, Omar M A El-Agnaf, Glenda Halliday, Deniz Kirik
BACKGROUND: Alpha-synuclein (asyn) has been shown to play an important role in the neuropathology of Parkinson's disease (PD). In the diseased brain, classic intraneuronal inclusions called Lewy bodies contain abnormal formations of asyn protein which is mostly phosphorylated at serine 129 (pS129 asyn). This suggests that post-translational modifications may play a role in the pathogenic process. To date, several uniplex assays have been developed in order to quantify asyn not only in the brain but also in cerebrospinal fluid and blood samples in order to correlate asyn levels to disease severity and progression...
2016: Molecular Neurodegeneration
Jianmin Chen, Yanping Chen, Graham Vail, Heiman Chow, Yang Zhang, Lauren Louie, Jiali Li, Ronald P Hart, Mark R Plummer, Karl Herrup
BACKGROUND: Our previous studies of Alzheimer's disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene...
2016: Molecular Neurodegeneration
Pierre De Rossi, Virginie Buggia-Prévot, Benjamin L L Clayton, Jared B Vasquez, Carson van Sanford, Robert J Andrew, Ruben Lesnick, Alexandra Botté, Carole Deyts, Someya Salem, Eshaan Rao, Richard C Rice, Angèle Parent, Satyabrata Kar, Brian Popko, Peter Pytel, Steven Estus, Gopal Thinakaran
BACKGROUND: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD...
2016: Molecular Neurodegeneration
Reiner Schneider, Barbara Koop, Friederike Schröter, Jason Cline, Jens Ingwersen, Carsten Berndt, Hans-Peter Hartung, Orhan Aktas, Tim Prozorovski
BACKGROUND: Disease progression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), as one of its animal models, is characterized by demyelination and neuronal damage in white and gray matter structures, including the hippocampus. It is thought that dysfunction of the hippocampus, a primary locus of learning and memory consolidation, may contribute to cognitive impairment in MS patients. Previously, we reported an increased generation of hippocampal neuronal progenitors in the acute stage of EAE, whereas the microenvironmental signals triggering this process remained uninvestigated...
2016: Molecular Neurodegeneration
Sandro Alves, Thibaut Marais, Maria-Grazia Biferi, Denis Furling, Martina Marinello, Khalid El Hachimi, Nathalie Cartier, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Martine Barkats, Annie Sittler
BACKGROUND: We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences of the genetic defect in this brain structure. RESULTS: LV-mediated overexpression of MUT ATXN7 into the cerebellum of C57/BL6 adult mice induced neuropathological features similar to that observed in patients, such as intranuclear aggregates in Purkinje cells (PC), loss of synaptic markers, neuroinflammation, and neuronal death...
2016: Molecular Neurodegeneration
Daniel M Mason, Negin Nouraei, Deepti B Pant, Kristin M Miner, Daniel F Hutchison, Kelvin C Luk, John F Stolz, Rehana K Leak
No abstract text is available yet for this article.
2016: Molecular Neurodegeneration
Alexander McGown, Dame Pamela J Shaw, Tennore Ramesh
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with death on average within 2-3 years of symptom onset. Mutations in superoxide dismutase 1 (SOD1) have been identified to cause ALS. Riluzole, the only neuroprotective drug for ALS provides life extension of only 3 months on average. Thishighlights the need for compound screening in disease models to identify new neuroprotective therapies for this disease. Zebrafish is an emerging model system that is well suited for the study of diseasepathophysiology and also for high throughput (HT) drug screening...
2016: Molecular Neurodegeneration
Jaekwang Kim, Fabienne C Fiesel, Krystal C Belmonte, Roman Hudec, Wang-Xia Wang, Chaeyoung Kim, Peter T Nelson, Wolfdieter Springer, Jungsu Kim
BACKGROUND: Loss-of-function mutations in PINK1 and PARKIN are the most common causes of autosomal recessive Parkinson's disease (PD). PINK1 is a mitochondrial serine/threonine kinase that plays a critical role in mitophagy, a selective autophagic clearance of damaged mitochondria. Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Therefore, identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD...
2016: Molecular Neurodegeneration
Min Jung Lee, So Jin Bing, Jonghee Choi, Minhee Jang, Gihyun Lee, Hyunkyoung Lee, Byung Soo Chang, Youngheun Jee, Sung Joong Lee, Ik-Hyun Cho
BACKGROUND: The inflammatory myeloid cell activation is one of the hallmarks of experimental autoimmune encephalomyelitis (EAE), yet the in vivo role of the inflammatory myeloid cell activation in EAE has not been clearly resolved. It is well-known that IKK/NF-κB is a key signaling pathway that regulates inflammatory myeloid activation. METHODS: We investigated the in vivo role of inflammatory myeloid cell activation in myelin oligodendrocyte glycoprotein (MOG) peptides-induced EAE using myeloid cell type-specific ikkβ gene conditional knockout-mice (LysM-Cre/Ikkβ (F/F) )...
2016: Molecular Neurodegeneration
Ramon Velazquez, Darren M Shaw, Antonella Caccamo, Salvatore Oddo
BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation...
2016: Molecular Neurodegeneration
Lan-Yan Lin, Jing Zhang, Xiao-Man Dai, Nai-An Xiao, Xi-Lin Wu, Zhen Wei, Wen-Ting Fang, Yuan-Gui Zhu, Xiao-Chun Chen
BACKGROUND: Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice...
2016: Molecular Neurodegeneration
Syed Faraz Kazim, Khalid Iqbal
Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology...
2016: Molecular Neurodegeneration
Holger Cynis, Jeffrey L Frost, Helen Crehan, Cynthia A Lemere
Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms...
2016: Molecular Neurodegeneration
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