Neurodegenerative Diseases

Publisher: Karger

Description

Neurodegenerative Diseases is a bimonthly, multidisciplinary journal for the publication of advances in the understanding of neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease and related neurological and psychiatric disorders. Neurodegenerative Diseases publishes results from basic and clinical scientific research programs designed to better understand the normal functions of genes and proteins involved in neurodegenerative diseases, to characterize their role in pathogenic disease mechanisms, to model their functions in animals and to explore their roles in the diagnosis, treatment and prevention of neurodegenerative diseases. It is our firm belief that successful strategies for novel treatments of neurodegenerative diseases will emerge from the intelligent integration of basic neurobiology with clinical sciences. Therefore, Neurodegenerative Diseases will accept high-quality papers from a broad spectrum of scientific research areas ranging from molecular and cell biology to neuroscience, pharmacology, genetics and the clinical sciences.

  • Impact factor
    3.41
  • 5-year impact
    3.02
  • Cited half-life
    3.90
  • Immediacy index
    0.92
  • Eigenfactor
    0.00
  • Article influence
    0.86
  • Website
    Neurodegenerative Diseases website
  • Other titles
    Neuro-degenerative diseases
  • ISSN
    1660-2862
  • OCLC
    260107464
  • Material type
    Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Karger

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • On author's server or institutional server
    • Server must be non-commercial
    • Publisher's version/PDF cannot be used
    • Publisher copyright and source must be acknowledged
    • Must link to publisher version
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Bexarotene, a retinoid X receptor agonist, has been shown to reverse neurodegeneration in mouse models of Alzheimer's disease (AD), accompanied by a decreased level of amyloid-β (Aβ), which is a hallmark of AD. However, the mechanism underlying this therapeutic effect may involve enhancing the sensitivity to insulin. Objective: This study was to test the hypothesis that bexarotene would protect against Aβ25-35-induced dysfunction through the insulin signaling pathway. Methods: Using a whole-cell patch clamp technique, the excitability and voltage-gated potassium currents of hippocampal neurons were examined in four groups of cells (control, Aβ, Aβ + bexarotene and bexarotene). Results: It was found that insulin increased the excitability of neurons. Bexarotene could enhance this effect and reverse the Aβ25-35-induced decrease in the firing rate of the action potential (AP). In addition, the properties of the single AP (sAP) and voltage-gated outward K(+) currents were recorded, which finally showed similar changes to those in the firing frequency. Conclusion: The effects of bexarotene on Aβ-impaired excitability and sAP duration were mainly associated with K(+) channels through insulin signaling pathway, which may be an additional mechanism underlying the protective effect of bexarotene on AD. © 2014 S. Karger AG, Basel.
    Neurodegenerative Diseases 04/2014;
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    ABSTRACT: Objective: Temporoparietal cortex thinning is associated with mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase in EEG upper/low α frequency power ratio has been associated with AD converter MCI subjects. We investigated the association of the EEG upper/low α frequency power ratio with patterns of cortical thickness in MCI. Methods: 74 adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalography (EEG) recording and high-resolution 3-dimensional magnetic resonance imaging (MRI). The EEG upper/low α frequency power ratio as well as cortical thickness were computed for each subject. Three MCI groups were detected according to increasing tertile values of EEG upper/low α frequency power ratios, and the difference of cortical thickness among the groups was estimated. Results: The EEG high upper/low α frequency power ratio group had a total cortical grey matter volume reduction of 471 mm(2), greater than that of the EEG low upper/low α frequency power ratio group (p < 0.001). The EEG high upper/low α frequency power ratio group showed a similar but less marked pattern (160 mm(2)) of cortical thinning when compared to the EEG middle upper/low α frequency power ratio group (p < 0.001). Moreover, the EEG high upper/low α frequency power ratio group had wider cortical thinning than other groups, mapped to the supramarginal gyrus and precuneus bilaterally. No significant regional cortical thickness differences were found between middle and low EEG upper/low α frequency power ratio groups. Conclusion: A high EEG upper/low α frequency power ratio was associated with temporoparietal cortical thinning in MCI subjects. The combination of upper/low α frequency power ratio and cortical thickness measurement could be useful for identifying individuals at risk for progression to AD dementia and may be of value in the clinical context. © 2014 S. Karger AG, Basel.
    Neurodegenerative Diseases 01/2014;
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    ABSTRACT: The time course and order of the pathological-physiological processes in Alzheimer's disease (AD) are still under investigation and it is expected that molecular imaging will provide important insight into early brain pathology. Multi-tracer positron emission tomography studies visualizing fibrillar amyloid, inflammatory changes including astrocytosis and activation of microglia as well as cerebral glucose metabolism indicate that AD pathological processes are initiated and ongoing decades before the onset of cognitive symptoms. Therefore, prevention might be a new promising target for AD therapy. © 2014 S. Karger AG, Basel.
    Neurodegenerative Diseases 01/2014;
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    ABSTRACT: Background: Animal models closely resembling the etiopathogenesis of Alzheimer's disease (AD) are needed for research on disease mechanisms and for drug development. No natural model of AD is available, so big hopes arose from transgenic and knockout technology, expecting that modulation and expression of pathogenetically important proteins resemble human brain pathology and functional deficits in the expected morphological and temporal pattern. Objective: The real usefulness of these models should be discussed from an objective point of view. Results: Not a single one of the published transgenic rodent models fulfils this hope, and even complex multiple transgenic animals do not suffer from real AD. It is crucial to be aware that all of the commonly used mice and rats are just models, and therefore results from drug efficacy testing have to be interpreted with care. Repeated experience with failed trials of new treatments that previously had been published as successful in animals has led to the wrong conclusion that animal models are of low predictive value or even of no use. Often clinical trials replicate exactly what was shown in the animal proof-of-concept studies. Conclusion: The value of animal models depends mainly on the careful experimentation and correct interpretation of results. Appropriate planning of experiments will help to increase the predictive value in drug development programs, though this may also increase negative findings. However, the early failure may enable a faster focus on more promising strategies. © 2014 S. Karger AG, Basel.
    Neurodegenerative Diseases 01/2014;
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    ABSTRACT: Background/Aims: Alleles of the FMR1 gene containing small expansions of the CGG-trinucleotide repeat comprise premutation and grey-zone alleles. Premutation alleles may cause late-onset Fragile X-associated tremor/ataxia syndrome attributed to the neurotoxic effect of elevated FMR1 transcripts. Our earlier data suggested that both grey-zone and low-end premutation alleles might also play a significant role in the acquisition of the parkinsonian phenotype due to mitochondrial dysfunction caused by elevated FMR1 mRNA toxicity. These data were obtained through clinical and molecular comparisons between carriers of grey-zone/low-end premutation alleles and group-matched non-carrier controls from patients with idiopathic Parkinson's disease (iPD). We aimed to explore the relationship between grey-zone alleles, parkinsonism and white matter changes. Methods: This study compared the extent and severity of white matter hyperintensity (WMH) on magnetic resonance imaging, using a semi-quantitative method, between 11 grey-zone/low-end premutation carriers and 20 non-carrier controls with iPD from our earlier study. Relationships between WMH scores, and cognitive and motor test scores were assessed for carriers and non-carriers. Results: Supratentorial WMH scores, and tremor and ataxia motor scores were significantly higher in carriers compared with disease controls. Moreover, some associations between cognitive decline and WMH scores were specific for each respective carrier status category. Conclusions: The results support our earlier claim that grey-zone alleles contribute to the severity of parkinsonism and white matter changes. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 12/2013;
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    ABSTRACT: In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 12/2013;
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    ABSTRACT: Backgound/Objective: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [(18)F]flutemetamol and the level of amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. Methods: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [(18)F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. Results: Four of the 17 patients (23.5%) had amyloid-β pathology based on the overall pathology read and also showed increased [(18)F]flutemetamol uptake. [(18)F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-β levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-β level and uptake of [(18)F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [(18)F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. Conclusions: [(18)F]Flutemetamol detects brain amyloid-β in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 11/2013;
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    ABSTRACT: Background: Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navβ2 cleavages and Nav1.1 levels. Objective: It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Navβ2 processing and Nav1.1 levels in neuronal cells. Methods: We first generated B104 rat neuroblastoma cells stably expressing Navβ2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Navβ2 processing and Nav1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively. Results: The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Navβ2 as compared to wtPS1 controls, both in cells and in a cell-free system. Nav1.1 mRNA and protein levels, as well as the surface levels of Nav channel α-subunits, were also significantly reduced in PS1(E280A) cells. Conclusion: Our data indicate that the FAD-linked PS1(E280A) mutation decreases Nav channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Navβ2 in neuronal cells. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 11/2013;
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    ABSTRACT: Background: Mutations in LRRK2 (leucine-rich repeat kinase 2) are a common cause of familial Parkinson's disease. However, the mechanisms through which LRRK2 mutations contribute to neurodegeneration are poorly understood. Objective: We investigated the effects of WT, G2019S (GS), R1441C (RC) and kinase dead LRRK2 across multiple different cellular compartments in order to gain insight into the breadth of LRRK2 effects on cellular function. Methods: Nematodes expressing lgg-1::RFP, hsp1::GFP, hsp4::GFP and hsp6::GFP were crossed to nematode lines expressing WT, GS, RC or kinase dead LRRK2. Results: We observed that GS and RC LRRK2 inhibited autophagy, while WT, GS and RC LRRK2 increased the response of the mitochondrial hsp6 reporter to stress. The response of the hsp reporters under basal conditions was more nuanced. Conclusion: These results support a putative role of LRRK2 in the autophagic and mitochondrial systems. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;
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    ABSTRACT: Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D3 on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-β peptide (Aβ) is significantly increased, which is caused by an increased β-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aβ level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D3. Our results further strengthen the link between AD and vitamin D3 and suggest that supplementation of vitamin D3 might have a beneficial effect in AD prevention. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;
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    ABSTRACT: Background: Presenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-β 42 (Aβ42) to Aβ40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of Aβ40 rather than increase that of Aβ42. Since it has been difficult to estimate Aβ42 secretion in brains of PS1-FAD patients due to substantial Aβ42 accumulation, it remains unknown whether the enhanced Aβ42 to Aβ40 ratio in brains of FAD patients is caused by elevated Aβ42 secretion or by reduced secretion of Aβ40. Objective/Methods: Cerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursor-like protein-1-derived Aβ-like peptide (APL1β), including APL1β28, an Aβ42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and Aβ42 secretion in the brain was estimated. Results: The relative ratio of CSF APL1β28 to total APL1β was higher in PS1-FAD patients than in controls. Importantly, CSF APL1β28 was not significantly higher. However, C-terminally shorter CSF APL1β25 and APL1β27 were significantly lower in PS1-FAD patients and, as expected, so were CSF Aβ40 and Aβ42. Conclusion: A higher relative ratio of the CSF Aβ42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive Aβ42 accumulation in the PS1-FAD brain occurs without an apparent increase in Aβ42 secretion. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;
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    ABSTRACT: Misfolding and pathogenic aggregation of α-synuclein (αSyn) is a hallmark of familial and sporadic Parkinson's disease, but the physiological state of the protein in cells remains unsettled. We have further examined our hypothesis that endogenous αSyn can occur in normal cells as a metastable, helically folded tetramer, not solely as the unfolded monomer long thought to be its native form. At this meeting, we reviewed our recent approaches for trapping αSyn in intact cells via in vivo crosslinking, a 5-step purification of αSyn from normal human brain, and the generation of new monoclonal antibodies to αSyn that enable general and oligomer-selective ELISAs. Crosslinking in intact living cells confirmed that αSyn occurs in the cytosol of neurons and non-neural cells in substantial part as metastable tetramers and related oligomers, plus varying amounts of free monomers. The non-pathogenic homolog, β-synuclein, forms closely similar oligomeric assemblies, suggesting that the oligomers we observe for αSyn are also physiological. In contrast to other normal oligomeric proteins (e.g., DJ-1), αSyn tetramers dissociate rapidly to monomers upon conventional cell lysis but are retained partially as tetramers if cells are lysed at high protein concentrations ('molecular crowding'). Thus, αSyn exists natively as helical tetramers that are in dynamic equilibrium with unfolded monomers. The tetramers appear relatively resistant to aggregation, in contrast to monomers, which may give rise to fibrillar inclusions. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;
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    ABSTRACT: Background: Accumulation of β-amyloid peptides (Aβ) and its progressive deposition into amyloid plaques are key events in the aetiology of Alzheimer's disease (AD). To date, AD treatment is symptomatic and consists of drugs treating the cognitive decline. Objective: Identifying molecules specifically targeting Aβ production or aggregation represents a huge challenge in the development of specific AD treatments. Several molecules reported as γ-secretase inhibitors or modulators have been evaluated, but so far none of them have proven to be selective or fully efficient. We have previously investigated the potential interest of plant extracts and we reported that Pterocarpus erinaceus stem-bark extract was active on Aβ release. Our aim here was to characterize the mechanisms by which this extract reduces Aβ levels. Methods: We tested P. erinaceus extract at non-toxic concentrations on cells expressing the human amyloid precursor protein (APP695) or its amyloidogenic β-cleaved C-terminal fragment (C99), as well as on neuronal cell lines. P. erinaceus extract was found to inhibit Aβ release. We further showed that this extract inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that P. erinaceus extract is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit γ-secretase-dependent Notch intracellular domain release. Conclusion: P. erinaceus extract appears as a new potent γ-secretase inhibitor selective towards APP processing. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that occurs in two clinically indistinguishable forms: sporadic (SALS) and familial (FALS), the latter linked to several gene mutations, mostly inheritable in a dominant manner. Nearly 20% of FALS forms are linked to mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Research on ALS relies on transgenic models and particularly on mice carrying a glycine-to-alanine conversion at the 93rd codon (G93A) of the hSOD1 gene. Although G93A transgenic mice have been widely employed in clinical trials and basic research, doubts have been recently raised from numerous reliable sources about their suitability to faithfully reproduce human disease. Besides, the scientific community has already foreseen swine as an attractive and alternative model to nonhuman primates for modeling human diseases due to closer anatomical, physiological and biochemical features of swine rather than rodents to humans. On this basis, we have produced the first swine ALS model by in vitro transfection of cultured somatic cells combined with somatic cell nuclear transfer (SCNT). To achieve this goal we developed a SOD1(G93A) (superoxide dismutase 1 mutated in Gly93-Ala) vector, capable of promoting a high and stable transgene expression in primary porcine adult male fibroblasts (PAF). After transfection, clonal selection and transgene expression level assessment, selected SOD1(G93A) PAF colonies were used as nuclei donors in SCNT procedures. SOD1(G93A) embryos were transferred in recipient sows, and pregnancies developed to term. A total of 5 piglets survived artificial hand raising and weaning and developed normally, reaching adulthood. Preliminary analysis revealed transgene integration and hSOD1(G93A) expression in swine tissues and 360° phenotypical characterization is ongoing. We believe that our SOD1(G93A) swine would provide an essential bridge between the fundamental work done in rodent models and the reality of treating ALS. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 10/2013;