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Does neuroinflammation fan the flame in neurodegenerative diseases?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative str...
Source: Molecular Neurodegeneration - November 16, 2009 Category: Neurology Authors: Tamy Frank-CannonLaura AltoFiona McAlpineMalu Tansey Source Type: journals

Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brainEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - November 4, 2009 Category: Neurology Authors: Karrie GrearI-Fang LingJames SimpsonJennifer FurmanChristopher SimmonsShawn PetersonFrederick SchmittWilliam MarkesberyQiang LiuJulia CrookSteven YounkinGuojun BuSteven Estus Source Type: journals

Neuroprotective effects of blockers for T-type calcium channelsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type calcium channel antagonists. The family of low-voltage activated, or T-type calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha 1G, alpha 1H, and alpha 1I. Among these three subunits, alpha 1H is highly expressed in hippocampus and certain cortical regions. However, T-type calcium channel blockers can protect neurons derived from alpha 1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the ...
Source: Molecular Neurodegeneration - October 28, 2009 Category: Neurology Authors: Norelle WildburgerAvary Lin-YeMichelle BairdDebin LeiJianxin Bao Source Type: journals

2009 international conference on molecular neurodegenerationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The objectives of this meeting were to (1) promote cutting-edge neurodegeneration research in China and in neighboring Asian countries; (2) facilitate the exchange of information relevant to neurodegenerative research; (3) provide education opportunity for students, postdocs and physicians; and (4) provide a platform for investigators at different career levels to interact and network, and to foster collaborations at the international levels. About 100 investigators presented their recent discoveries with a wide range of scopes of neurodegeneration research, including new genes, molecular pathways, animal models, and poten...
Source: Molecular Neurodegeneration - October 27, 2009 Category: Neurology Authors: Yunwu ZhangLisa OwensGuojun Bu Source Type: journals

CD74 interacts with APP and suppresses the production of AbetaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Taken together, we propose that CD74 inhibits Abeta production by interacting with and derailing normal trafficking of APP. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - October 21, 2009 Category: Neurology Authors: Shuji MatsudaYukiko MatsudaLuciano D'Adamio Source Type: journals

Dietary composition modulates brain mass and amyloid beta levels in a mouse model of aggressive Alzheimer's amyloid pathologyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
ObjectiveAlzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods: From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fa...
Source: Molecular Neurodegeneration - October 20, 2009 Category: Neurology Authors: Steve PedriniCarlos ThomasHannah BrautigamJames SchmeidlerLap HoPaul FraserDavid WestawayPeter St George HyslopRalph MartinsJoseph BuxbaumGiulio PasinettiDara DicksteinPatrick HofMichelle EhrlichSam Gandy Source Type: journals

Development of monoclonal antibodies and quantitative ELISAs targeting insulin-degrading enzymeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: We succeeded in developing novel mAbs that selectively detect rodent and/or human IDE, which we have shown to be suitable for a wide range of applications, including western blotting, immunoprecipitation, immunocytochemistry, immunohistochemistry, and quantitative sandwich ELISAs. These novel anti-IDE mAbs and the assays derived from them constitute important new tools for addressing many unresolved questions about the basic biology of IDE and its role in multiple highly prevalent human diseases. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - October 15, 2009 Category: Neurology Authors: Anthony DelleDonneNaomi KouriLael ReinstatlerTomoko SaharaLilin LiJi ZhaoDennis DicksonNilufer Ertekin-TanerMalcolm Leissring Source Type: journals

Parkinson's Disease Brain Mitochondria Have Impaired Respirasome Assembly, Age-Related Increases in Distribution of Oxidative Damage to mtDNA and No Differences in Heteroplasmic mtDNA Mutation AbundanceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: sPD brain mitochondria have reduced mitochondrial respiratory protein levels in complexes I-V, implying a generalized defect in respirasome assembly. These deficiencies do not appear to arise from altered point mutational burden in mtDNA or reduction of nuclear signaling for mitochondrial biogenesis, implying downstream etiologies. The origin of age-related increases in distribution of oxidative mtDNA damage in sPD but not CTL brains is not clear, tracks with but does not determine the sPD phenotype, and may indicate a unique consequence of aging present in sPD that could contribute to mtDNA deletion generatio...
Source: Molecular Neurodegeneration - September 22, 2009 Category: Neurology Authors: Charles ArthurStephanie MortonLisa DunhamPaula KeeneyJames Bennett Source Type: journals

Upregulation of miRNA hsa-miR-342-3p in experimental and idiopathic prion diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The aim of our study was to analyze the differential expression of miRNAs in the brains of BSE-infected cynomolgus macaques as a model for Creutzfeldt-Jakob disease (CJD). MicroRNAs (miRNAs) are small noncoding RNAs regulating gene expression by mRNA targeting. Among other functions they contribute to neuronal development and survival. Recently, the lack of miRNA processing has been shown to promote neurodegeneration and deregulation of several miRNAs has been reported to be associated with Scrapie in mice. Therefore, we hypothesized that miRNAs are also regulated in response to human prion disease. We have applied miRNA-m...
Source: Molecular Neurodegeneration - August 26, 2009 Category: Neurology Authors: Judith MontagReiner HittLennart OpitzWalter Schulz-SchaefferGerhard HunsmannDirk Motzkus Source Type: journals

Apolipoprotein E4(1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: ApoE4(1-272) fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1-272) fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - August 19, 2009 Category: Neurology Authors: Toshiyuki NakamuraAtsushi WatanabeTakahiro FujinoTakashi HosonoMakoto Michikawa Source Type: journals

Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neuronsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: We have developed and evaluated novel conditional alpha-synuclein transgenic mice with transgene expression directed selectively to nigrostriatal dopaminergic neurons as a potential new mouse model of PD. Our data support the pathophysiological relevance of C-terminally truncated alpha-synuclein species in vivo. The expression of alpha-Syn119 in the mouse nigrostriatal dopaminergic pathway may provide a useful model of striatal dopamine depletion and could potentially provide a presymptomatic model of PD perhaps representative of the earliest derangements in dopaminergic neuronal function observed prior to neu...
Source: Molecular Neurodegeneration - July 23, 2009 Category: Neurology Authors: Joao Paulo DaherMingyao YingRebecca BanerjeeRebecca McDonaldMyriam Dumas HahnLichuan YangM. Flint BealBobby ThomasValina DawsonTed DawsonDarren Moore Source Type: journals

Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and al...
Source: Molecular Neurodegeneration - July 22, 2009 Category: Neurology Authors: Bo SuHaihua LiuXinglong WangShu ChenSandra SiedlakEisaku KondoRaymond ChoiAtsushi TakedaRudy CastellaniGeorge PerryMark SmithXiongwei ZhuHyoung-gon Lee Source Type: journals

Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptideEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: These data suggest that acyl peptide hydrolase is involved in the degradation of oligomeric amyloid-beta, an activity that, if induced, might present a new tool for therapy aimed at reducing neurodegeneration in the Alzheimer's brain. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - July 22, 2009 Category: Neurology Authors: Rina YaminCheng ZhaoPeter O'ConnorAnn McKeeCarmela Abraham Source Type: journals

Experimental models for the study of neurodegeneration in amyotrophic lateral sclerosisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause, characterized by the selective and progressive death of both upper and lower motoneurons, leading to a progressive paralysis. Experimental animal models of the disease may provide knowledge of the pathophysiological mechanisms and allow the design and testing of therapeutic strategies, provided that they mimic as close as possible the symptoms and temporal progression of the human disease. The principal hypotheses proposed to explain the mechanisms of motoneuron degeneration have been studied mostly in models in vitro, such as primar...
Source: Molecular Neurodegeneration - July 19, 2009 Category: Neurology Authors: Luis Tovar-y-RomoLuz Diana Santa-CruzRicardo Tapia Source Type: journals

Correction: Dissembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patientsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Correction to Nural H, He P, Beach T, Sue L, Xia W, Shen Y. Dissembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patients Molecular Neurodegeneration 2009, 4:23. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - July 14, 2009 Category: Neurology Authors: Zhenyu ZhongHikmet NuralPing HeGina CivarellaThomas BeachLucia SueCharles AdlerHolly ShillJohn CavinessWeiming XiaYong Shen Source Type: journals

Nucleation of protein aggregation kinetics as a basis for genotype-phenotype correlations in polyglutamine diseasesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recent studies of inherited neurodegenerative disorders have suggested a linkage between the propensity toward aggregation of mutant protein and disease onset. This is particularly apparent for polyglutamine (polyQ) diseases caused by expansion of CAG-trinucleotide repeats. However, a quantitative framework for relating aggregation kinetics with molecular mechanisms of neurodegeneration initiation is lacking. Here, using the repeat-length-dependent age-of-onset in polyQ diseases, we derived a mathematical model based on nucleation of aggregation kinetics to describe genotype-phenotype correlations, and validated the model ...
Source: Molecular Neurodegeneration - July 14, 2009 Category: Neurology Authors: Keizo SugayaShiro Matsubara Source Type: journals

The interactome of the Amyloid betaeta Precursor Protein family members is shaped by phosphorylation of their intracellular domainsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Our data indicates that APP can regulate diverse cellular processes and that, vice versa, a network of signaling events can impact APP processing. Our results also suggest that phosphorylation of the APP Intracellular Domain will dramatically shape the APP interactome and, consequently, will regulate APP processing, APP transport and APP/AID-mediated functions. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - July 13, 2009 Category: Neurology Authors: Robert TamayevDawang ZhouLuciano D'Adamio Source Type: journals

Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependenceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Extensive genetic, biochemical, and histological evidence has implicated the amyloid-beta peptide (Abeta) in Alzheimer's disease pathogenesis, and several mechanisms have been suggested, such as metal binding, reactive oxygen species production, and membrane pore formation. However, recent evidence argues for an additional role for signaling mediated by the amyloid precursor protein, APP, in part via the caspase cleavage of APP at aspartate 664. Here we review the effects and implications of this cleavage event, and propose a model of Alzheimer's disease that focuses on the critical nature of this cleavage and its downstre...
Source: Molecular Neurodegeneration - June 25, 2009 Category: Neurology Authors: Dale Bredesen Source Type: journals

Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Background: It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria supply the adenosine triphosphate (ATP) needed to support axonal transport and contribute to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and...
Source: Molecular Neurodegeneration - June 16, 2009 Category: Neurology Authors: Patricia TrimmerKathleen SchwartzM. Kathleen BorlandLuis De TaboadaJackson StreeterUri Oron Source Type: journals

Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - June 15, 2009 Category: Neurology Authors: Javorina MilosevicSigrid SchwarzVera OgunladeAnne MeyerAlexander StorchJohannes Schwarz Source Type: journals

Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangleEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidativ...
Source: Molecular Neurodegeneration - June 5, 2009 Category: Neurology Authors: Kristen MalkusElpida TsikaHarry Ischiropoulos Source Type: journals

Dissembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patientsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The PARK7 gene encodes a protein, DJ-1, with several functions for the protection of cells from oxidative stress, sperm maturation and fertilization, and chaperone activity. Mutations in the PARK7 gene are associated with autosomal recessive early-onset Parkinson's disease (PD). DJ-1 has been reported to be expressed in multiple cells in the central nervous system. By using both native and denatured Western blots, we examined the levels of total DJ-1 and High molecular weight complexes of DJ-1 (HMW) compared in both the substantia nigra and cortex from rapidly autopsied 18 PD and 9 non-pathological control (NPC) brains. We...
Source: Molecular Neurodegeneration - June 4, 2009 Category: Neurology Authors: Hikmet NuralPing HeThomas BeachLucia SueWeiming XiaYong Shen Source Type: journals

An exo-cell assay for examining real-time gamma-secretase activity and inhibitionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
gamma-Secretase is an aspartyl protease that cleaves multiple substrates that are involved in broad biological processes ranging from stem cell development to neurodegeneration. The investigation of gamma-secretase has been limited by currently available assays that require genetic or biochemical manipulation in the form of substrate transfection or membrane preparation. Here we report an exo-cell assay that is capable of characterizing gamma-secretase activity in any cellular system without limitation. Using a highly active, recombinant substrate this assay can quickly and easily ascertain the status of gamma-secretase ac...
Source: Molecular Neurodegeneration - June 2, 2009 Category: Neurology Authors: Christopher SheltonYuan TianMark FrattiniYue-Ming Li Source Type: journals

Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The gamma-secretase complex is a major therapeutic target for the prevention and treatment of Alzheimer's disease. Previous studies have shown that treatment of young APP mice with specific inhibitors of gamma-secretase prevented formation of new plaques. It has not yet been shown directly whether existing plaques would be affected by gamma-secretase inhibitor treatment. Similarly, alterations in neuronal morphology in the immediate vicinity of plaques represent a plaque-specific neurotoxic effect. Reversal of these alterations is an important endpoint of successful therapy whether or not a treatment affects plaque size. ...
Source: Molecular Neurodegeneration - May 6, 2009 Category: Neurology Authors: Monica Garcia-Alloza, Meenakshi Subramanian, Diana Thyssen, Laura A Borrelli, Abdul Fauq, Pritam Das, Todd E Golde, Bradley T Hyman and Brian J Bacskai Source Type: journals

Calcium signaling in neurodegenerationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled home...
Source: Molecular Neurodegeneration - May 6, 2009 Category: Neurology Authors: Philippe Marambaud, Ute Dreses-Werringloer and Valerie Vingtdeux Source Type: journals

LRP1 shedding in human brain: roles of ADAM10 and ADAM17Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Our results demonstrate that LRP1 is shed by ADAM10 and ADAM17 and functional sLRP1 is abundantly present in human brain and CSF. Dysregulated LRP1 shedding during aging could alter its function and may contribute to the pathogenesis of AD. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - April 16, 2009 Category: Neurology Authors: Qiang Liu, Juan Zhang, Hien Tran, Marcel M. Verbeek, Karina Reiss, Steven Estus and Guojun Bu Source Type: journals

All-you-can-eat: autophagy in neurodegeneration and neuroprotectionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Autophagy is the major pathway involved in the degradation of proteins and organelles, cellular remodeling, and survival during nutrient starvation. Autophagosomal dysfunction has been implicated in an increasing number of diseases from cancer to bacterial and viral infections and more recently in neurodegeneration. While a decrease in autophagic activity appears to interfere with protein degradation and possibly organelle turnover, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models. On the other hand, too much autophagic ...
Source: Molecular Neurodegeneration - April 6, 2009 Category: Neurology Authors: Philipp A Jaeger and Tony Wyss-Coray Source Type: journals

Calnuc plays a role in dynamic distribution of G alpha i but not G beta subunits and modulates ACTH secretion in AtT-20 neuroendocrine secretory cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In AtT-20 cells ACTH secretion is regulated by both Ca2+ and G proteins. We previously demonstrated that calnuc, an EF-hand Ca2+ binding protein which regulates Alzheimer's beta-amyloid precursor protein (APP) biogenesis, binds both Ca2+ as well as G alpha subunits. Here we investigate calnuc's role in G protein-mediated regulation of ACTH secretion in AtT-20 neuroendocrine secretory cells stably overexpressing calnuc-GFP. Similar to endogenous calnuc, calnuc-GFP is mainly found in the Golgi, on the plasma membrane (PM), and associated with regulated secretion granules (RSG). By deconvolution immunofluorescence, calnuc-GFP...
Source: Molecular Neurodegeneration - March 25, 2009 Category: Neurology Authors: Ping Lin, Thierry Fischer, Christine Lavoie, Haining Huang and Marilyn GIST Farquhar Source Type: journals

The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle eventsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Abeta) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Abeta species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic mouse primary...
Source: Molecular Neurodegeneration - March 16, 2009 Category: Neurology Authors: Kiran Bhaskar, Megan Miller, Alexandra Chludzinski, Karl Herrup, Michael Zagorski and Bruce T Lamb Source Type: journals

The role of tau in neurodegenerationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation) confer toxicity. Though data obtained from expe...
Source: Molecular Neurodegeneration - March 11, 2009 Category: Neurology Authors: Tania F Gendron and Leonard Petrucelli Source Type: journals

Increased DJ-1 Expression under Oxidative Stress and in Alzheimer's Disease BrainsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mutations in the DJ-1 gene have been linked to autosomal recessive familial Parkinson's disease. To understand the function of DJ-1, we determined the DJ-1 expression in both zebrafish and post mortem human brains. We found that DJ-1 was expressed early during zebrafish development and throughout adulthood. Knock down (KD) of DJ-1 by injection of morpholino did not cause dramatic morphologic alterations during development, and no loss of dopaminergic neurons was observed in embryos lacking DJ-1. However, DJ-1 KD embryos were more susceptible to programmed cell death. While a slight reduction in staining for islet-1 positi...
Source: Molecular Neurodegeneration - February 25, 2009 Category: Neurology Authors: Stephanie Baulac, Hope Lu, Jennifer Strahle, Ting Yang, Matthew S Goldberg, Jie Shen, Michael G Schlossmacher, Cynthia A Lemere, Qun Lu and Weiming Xia Source Type: journals

Inducible mutant huntingtin expression in HN10 cells reproduces Huntington's disease-like neuronal dysfunctionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: We developed neuronal cell lines with inducible expression of wild type and mutant huntingtin. These new cell lines represent a reliable in vitro system for modeling Huntington's disease and should find wide use for high-throughput screening application and for investigating the biology of mutant huntingtin. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - February 9, 2009 Category: Neurology Authors: Andreas Weiss, Ana Roscic and Paolo Paganetti Source Type: journals

PGC-1alpha as modifier of onset age in Huntington diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In more than 400 HD patients, a polymorphism located within...
Source: Molecular Neurodegeneration - February 6, 2009 Category: Neurology Authors: Elahe Taherzadeh-Fard, Carsten Saft, Jurgen Andrich, Stefan Wieczorek and Larissa Arning Source Type: journals

The gene coding for PGC-1α modifies age at onset in Huntington's DiseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction...
Source: Molecular Neurodegeneration - January 8, 2009 Category: Neurology Authors: Patrick Weydt, Selma M Soyal, Cinzia Gellera, Stefano DiDonato, Claus Weidinger, Hannes Oberkofler, G Bernhard Landwehrmeyer and Wolfgang Patsch Source Type: journals

The gene coding for PGC-1alpha modifies age at onset in Huntington's DiseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Huntington's disease (HD) is one of the most common autosomal dominant inherited neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction ...
Source: Molecular Neurodegeneration - January 8, 2009 Category: Neurology Authors: Patrick Weydt, Selma M. Soyal, Cinzia Gellera, Stefano DiDonato, Claus Weidinger, Hannes Oberkofler, Bernhard Landwehrmeyer and Wolfgang Patsch Source Type: journals

Detergent resistant membrane-associated IDE in cultured cells and brain tissue: Relevance to Abeta and insulin degradationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Our results support the notion that optimal substrate degradation by IDE may require its association with organized-DRMs. Alternatively, DRMs but not other plasma membrane regions, may act as platforms where Abeta accumulates, due to its hydrophobic properties, reaching local concentration close to its Km for IDE facilitating its clearance. Structural integrity of DRMs may also be required to tightly retain insulin receptor and IDE for insulin proteolysis. The concept that mis-location of Abeta degrading proteases away from DRMs may impair the physiological turn-over of Abeta in vivo deserves further investiga...
Source: Molecular Neurodegeneration - December 31, 2008 Category: Neurology Authors: Ayelen Bulloj, Maria C Leal, Ezequiel I Surace, Xue Zhang, Huaxi Xu, Maria D Ledesma, Eduardo M Castano and Laura Morelli Source Type: journals

Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Subacute rotenone treatment of differentiated SH-SY5Y neuroblastoma cells causes process retraction and partial death over several weeks, slowed mitochondrial movement in processes and appears to reproduce the Lewy neuritic changes of early Parkinson's disease pathology but does not cause Lewy body inclusions. The overall pattern of transcriptional regulation is gene under-expression with minimal regulation of ETC genes in spite of rotenone's being a complex I toxin. This rotenone-SH-SY5Y model in a differentiated human neural cell mimics changes of early Parkinson's disease may be useful for screening therape...
Source: Molecular Neurodegeneration - December 29, 2008 Category: Neurology Authors: M Kathleen Borland, Patricia A Trimmer, Jeremy D Rubinstein, Paula M Keeney, K P Mohanakumar, Lei Liu and James P Bennett Source Type: journals

Evaluation of Dimebon in cellular model of Huntington's diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Our results suggest that Ca2+ and mitochondria stabilizing effects may, in part, be responsible for beneficial clinical effects of Dimebon. However, the high concentrations of Dimebon required to achieve Ca2+ stabilizing and neuroprotective effects in our in vitro studies (50 uM) indicate that properties of Dimebon as cognitive enhancer are most likely due to potent inhibition of H1 histamine receptors. It is also possible that Dimebon acts on novel high affinity targets not present in cultured MSN preparation. Unbiased evaluation of Dimebon against a set of biochemical targets indicated that Dimebon efficien...
Source: Molecular Neurodegeneration - October 21, 2008 Category: Neurology Authors: Jun Wu, Qin Li and Ilya Bezprozvanny Source Type: journals

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - October 21, 2008 Category: Neurology Authors: Thuzar Shin, J. MARIO Isas, Chia-Ling Hsieh, Rakez Kayed, Charles G. Glabe, Ralf Langen and Jeannie Chen Source Type: journals

Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional roleEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: Overall, these data suggest that the release of the APP intracellular domain may modulate the sensitivity of neuronal cells to toxic stimuli, and that a transcriptional role of AID could be inscribed in signaling pathways thatare not activated in basal conditions. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - September 2, 2008 Category: Neurology Authors: Luca Giliberto, Dawang Zhou, Richard Weldon, Elena Tamagno, Pasquale De Luca, Massimo Tabaton and Luciano D'Adamio Source Type: journals

The role of Wnt signaling in neuronal dysfunction in Alzheimer's DiseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - July 24, 2008 Category: Neurology Authors: Nibaldo C Inestrosa and Enrique M Toledo Source Type: journals

Autoimmune-induced preferential depletion of myelin-associated glycoprotein (MAG) is genetically regulated in relapsing EAE (B6 × SJL) F1 miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: Taken together, our results show genetically controlled distinct patterns of MOG and MAG depletion, in MOG35–55 induced EAE in H-2b and H-2b/s mice. The data also suggest distinctive immune regulation of acute lesions that develop in relapsing compared to disease onset. A profound depletion of MAG, concomitant with marked depletion of axonal NF160, and sharp elevation of PARPp85 levels, occurred exclusively in relapsing H-2b/s mice. Our findings suggest concurrence of sharp decrease of MAG levels, axonal dysfunction and irreversible apoptosis with severe relapsing disease in H-2b/s mice. We propose that MOG-i...
Source: Molecular Neurodegeneration - June 9, 2008 Category: Neurology Authors: Dusanka S Skundric, Rujuan Dai, Vaagn L Zakarian and Weili Zhou Source Type: journals

Changes in γ-secretase activity and specificity caused by the introduction of consensus aspartyl protease active motif in Presenilin 1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study provides an important structural clue for the rational design of drugs to inhibit processing of APP at the γ-site without interfering with Notch processing. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - May 12, 2008 Category: Neurology Authors: Donald B Carter, Edwige Dunn, Adele M Pauley, Denise D McKinley, Timothy J Fleck, Brenda R Ellerbrook, Nancy C Stratman, Xiangdong Zhou, Carol S Himes, Jeffrey S Nye, Alfredo Tomasselli and Riqiang Yan Source Type: journals

A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: Taken together, we have identified a novel brain-enriched RING finger E3 ligase, which was up regulated in AD brains and neuronal cells exposed to injurious insults. It interacted with ATP6V0C protein suggesting that it may play a very specific role in controlling the turnover of an essential component of neurotransmitter release machinery. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - February 25, 2008 Category: Neurology Authors: Qing Yan Liu, Joy X Lei, Marianna Sikorska and Rugao Liu Source Type: journals

Presenilins are required for maintenance of neural stem cells in the developing brainEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The early embryonic lethality of mutant mice bearing germ-line deletions of both presenilin genes precluded the study of their functions in neural development. We therefore employed the Cre-loxP technology to generate presenilin conditional double knockout (PS cDKO) mice, in which expression of both presenilins is inactivated in neural progenitor cells (NPC) or neural stem cells and their derivative neurons and glia beginning at embryonic day 11 (E11). In PS cDKO mice, dividing NPCs labeled by BrdU are decreased in number beginning at E13.5. By E15.5, fewer than 20% of NPCs remain in PS cDKO mice. The depletion of NPCs is ...
Source: Molecular Neurodegeneration - January 8, 2008 Category: Neurology Authors: Woo-Young Kim and Jie Shen Source Type: journals

Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF in phorbol/PKC-activated Alzheimer APP ectodomain sheddingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - December 9, 2007 Category: Neurology Authors: Annat F Ikin, Mirsada Causevic, Steve Pedrini, Lyndsey S. Benson, Joseph D. Buxbaum, Toshiharu Suzuki, Simon Lovestone, Shigeki Higashiyama, Tomas Mustelin, Robert D. Burgoyne and Sam Gandy Source Type: journals

The Alzheimer's disease Beta-secretase enzyme, BACE1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the beta-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that beta-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of beta-amyloid. BACE1 knockout mice do not produce beta-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory defic...
Source: Molecular Neurodegeneration - November 15, 2007 Category: Neurology Authors: Sarah L Cole and Robert Vassar Source Type: journals

Design of a novel quantitative PCR (QPCR)-based protocol for genotyping mice carrying the neuroprotective Wallerian degeneration slow (Wlds) geneEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: We have developed a QPCR genotyping method that permits rapid and effective genotyping of Wlds copy number. This technique will be of particular benefit in studies where Wlds mice are cross-bred with other mouse models of neurodegenerative disease in order to understand the neuroprotective processes conferred by the Wlds mutation. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - October 30, 2007 Category: Neurology Authors: Thomas M Wishart, Stephen HF MacDonald, Philip E Chen, Michael J Shipston, Michael P Coleman, Thomas H Gillingwater and Richard R Ribchester Source Type: journals

Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatmentEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusions: The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of A-beta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD. (Source: Molecular Neurodegeneration)
Source: Molecular Neurodegeneration - October 22, 2007 Category: Neurology Authors: Iliya Lefterov, Angie Bookout, Zhu Wang, Matthias Staufenbiel, David Mangelsdorf and Radosveta Koldamova Source Type: journals