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1.
Workplace Health Saf ; 69(12): 548-555, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34167396

ABSTRACT

BACKGROUND: Long-term absenteeism continues to rise in Belgium and musculoskeletal disorders (MSDs) have been considered a primary cause. However, there is still uncertainty about the prevalence of MSDs, and about the contribution of work-related factors in the etiology of MSDs. SALTSA, which was developed in 2001, is a European diagnostic criterion document that aims to standardize the reporting of work-related upper limb MSDs (ULMSDs). The purpose of this work-site study was to implement SALTSA in daily occupational health practice and to determine the prevalence of ULMSDs in a Belgian company. METHODS: During health examinations, occupational health nurses and an occupational health physician screened employees in a company with ergonomically high-risk activities for the occurrence of ULMSDs using the SALTSA protocol. In order to explore associations between ULMSDs and lifestyle and work-related factors, bivariate and logistic regression analyses were performed. FINDINGS: Three hundred and eight (94.0%, 308/328) employees were screened resulting in an ULMSD prevalence of 20.5% (95% CI = [16.0-25.3]). Rotator cuff syndrome was the most common condition. Prevalence varied significantly between men (9.6%, 95% CI = [5.6-14.9]) and women (35.0%, 95% CI = [26.9-43.9]). Being female (p < .001) and working in the cabling assembly unit (p = .002) were found to be significant predictors of ULMSDs. CONCLUSION/APPLICATION TO PRACTICE: By using the SALTSA protocol in occupational health practices, ULMSDs can be screened unequivocally, enabling comparisons between different occupational sectors and countries. Occupational health nurses can play an important role in detecting and screening MSDs among workers.


Subject(s)
Musculoskeletal Diseases , Occupational Diseases , Belgium/epidemiology , Female , Humans , Male , Musculoskeletal Diseases/epidemiology , Occupational Diseases/epidemiology , Prevalence , Risk Factors , Upper Extremity , Workplace
2.
Blood ; 136(10): 1161-1168, 2020 09 03.
Article in English | MEDLINE | ID: mdl-32391884

ABSTRACT

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.


Subject(s)
Methotrexate/analogs & derivatives , Neoplasm Recurrence, Local/pathology , Peptide Synthases/genetics , Polyglutamic Acid/analogs & derivatives , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Tetrahydrofolate Dehydrogenase/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genome-Wide Association Study , Humans , Infant , Infant, Newborn , Male , Methotrexate/administration & dosage , Methotrexate/metabolism , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Polyglutamic Acid/administration & dosage , Polyglutamic Acid/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Prognosis , Young Adult
3.
Haematologica ; 104(3): 556-563, 2019 03.
Article in English | MEDLINE | ID: mdl-30467200

ABSTRACT

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10-8). Moreover, rs13228878 (OR=0.61; P=7.1×10-6) and rs10273639 (OR=0.62; P=1.1×10-5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.


Subject(s)
Antineoplastic Agents/adverse effects , Asparaginase/adverse effects , Genetic Variation , Pancreatitis/etiology , Polyethylene Glycols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Trypsin/genetics , Trypsinogen/genetics , Adolescent , Alleles , Antineoplastic Agents/administration & dosage , Asparaginase/administration & dosage , Child , Child, Preschool , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Infant , Male , Models, Biological , Phenotype , Polyethylene Glycols/administration & dosage , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
4.
Leukemia ; 32(12): 2527-2535, 2018 12.
Article in English | MEDLINE | ID: mdl-30201983

ABSTRACT

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (wm) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wmDNA-TG/wmEry-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 10-10, minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P = 8.4 × 10-6 and 1.3 × 10-3, respectively). The association was mostly driven by differences in wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.


Subject(s)
5'-Nucleotidase/genetics , Germ Cells/metabolism , Polymorphism, Single Nucleotide/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Adolescent , Antimetabolites, Antineoplastic/therapeutic use , Child , Child, Preschool , DNA/metabolism , Female , Gene Frequency/drug effects , Gene Frequency/genetics , Genome-Wide Association Study/methods , Genotype , Humans , Infant , Male , Mercaptopurine/therapeutic use , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Recurrence , Thioguanine/metabolism
5.
Nature ; 548(7665): 87-91, 2017 08 03.
Article in English | MEDLINE | ID: mdl-28746312

ABSTRACT

Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.


Subject(s)
Genetic Variation/genetics , Genetics, Population/standards , Genome, Human/genetics , Genomics/standards , Sequence Analysis, DNA/standards , Adult , Alleles , Child , Chromosomes, Human, Y/genetics , Denmark , Female , Haplotypes/genetics , Humans , Major Histocompatibility Complex/genetics , Male , Maternal Age , Mutation Rate , Paternal Age , Point Mutation/genetics , Reference Standards
6.
Mol Biol Cell ; 28(12): 1601-1611, 2017 Jun 15.
Article in English | MEDLINE | ID: mdl-28450455

ABSTRACT

Faithful segregation of chromosomes during cell division relies on multiple processes such as chromosome attachment and correct spindle positioning. Yet mitotic progression is defined by multiple parameters, which need to be quantitatively evaluated. To study the spatiotemporal control of mitotic progression, we developed a high-content analysis (HCA) approach that combines automated fluorescence microscopy with real-time quantitative image analysis and allows the unbiased acquisition of multiparametric data at the single-cell level for hundreds of cells simultaneously. The Mitotic Analysis and Recording System (MAARS) provides automatic and quantitative single-cell analysis of mitotic progression on an open-source platform. It can be used to analyze specific characteristics such as cell shape, cell size, metaphase/anaphase delays, and mitotic abnormalities including spindle mispositioning, spindle elongation defects, and chromosome segregation defects. Using this HCA approach, we were able to visualize rare and unexpected events of error correction during anaphase in wild-type or mutant cells. Our study illustrates that such an expert system of mitotic progression is able to highlight the complexity of the mechanisms required to prevent chromosome loss during cell division.


Subject(s)
Chromosome Segregation/physiology , Image Processing, Computer-Assisted/methods , Single-Cell Analysis/methods , Cell Cycle Proteins/genetics , Chromosome Segregation/genetics , Kinetochores/physiology , Mitosis/genetics , Mitosis/physiology , Saccharomycetales/genetics , Schizosaccharomyces/genetics , Software , Spatio-Temporal Analysis , Spindle Apparatus/physiology
7.
Nucleic Acids Res ; 44(D1): D38-47, 2016 Jan 04.
Article in English | MEDLINE | ID: mdl-26538599

ABSTRACT

Life sciences are yielding huge data sets that underpin scientific discoveries fundamental to improvement in human health, agriculture and the environment. In support of these discoveries, a plethora of databases and tools are deployed, in technically complex and diverse implementations, across a spectrum of scientific disciplines. The corpus of documentation of these resources is fragmented across the Web, with much redundancy, and has lacked a common standard of information. The outcome is that scientists must often struggle to find, understand, compare and use the best resources for the task at hand.Here we present a community-driven curation effort, supported by ELIXIR-the European infrastructure for biological information-that aspires to a comprehensive and consistent registry of information about bioinformatics resources. The sustainable upkeep of this Tools and Data Services Registry is assured by a curation effort driven by and tailored to local needs, and shared amongst a network of engaged partners.As of November 2015, the registry includes 1785 resources, with depositions from 126 individual registrations including 52 institutional providers and 74 individuals. With community support, the registry can become a standard for dissemination of information about bioinformatics resources: we welcome everyone to join us in this common endeavour. The registry is freely available at https://bio.tools.


Subject(s)
Computational Biology , Registries , Data Curation , Software
8.
ACS Chem Neurosci ; 6(4): 559-69, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25611616

ABSTRACT

The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aß) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aß peptide. Compounds which retained alkaline properties and high affinity for acidic cell compartments were the most effective. The present study demonstrates that (1) the amino side chain of chloroquine can be efficiently substituted by a bis(alkylamino)piperazine chain, (2) the quinoline nucleus can be replaced by a benzyl or a benzimidazole moiety, and (3) pharmacomodulation of the chemical structure allows the redirection of APP metabolism toward a decrease of Aß peptide release, and increased stability of APP-CTFs and amyloid intracellular fragment. Moreover, the benzimidazole compound 29 increases APP-CTFs in vivo and shows promising activity by the oral route. Together, this family of compounds retains a lysosomotropic activity which inhibits lysosome-related Aß production, and is likely to be beneficial for therapeutic applications in AD.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Chloroquine/analogs & derivatives , Neuroprotective Agents/chemistry , Quinolines/chemistry , Amyloid beta-Peptides/metabolism , Animals , Blotting, Western , Cell Death/drug effects , Cell Line, Tumor , Chloroquine/chemistry , Chloroquine/pharmacology , Drug Design , Female , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Neuroprotective Agents/pharmacology , Peptide Fragments/metabolism , Protein Stability/drug effects , Quinolines/pharmacology , Water/chemistry
9.
Aging Cell ; 12(1): 11-23, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23082852

ABSTRACT

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.


Subject(s)
Alzheimer Disease/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/physiology , tau Proteins/genetics , Alzheimer Disease/genetics , Animals , Brain-Derived Neurotrophic Factor/pharmacology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Synaptic Transmission/drug effects , Transgenes , tau Proteins/biosynthesis
10.
Curr Alzheimer Res ; 9(4): 397-405, 2012 May.
Article in English | MEDLINE | ID: mdl-22272619

ABSTRACT

Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.


Subject(s)
Alzheimer Disease/immunology , Alzheimer Disease/therapy , Immunotherapy, Active/methods , Mutation/genetics , Serine/metabolism , tau Proteins/metabolism , Age Factors , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Antibodies/blood , Cognition Disorders/etiology , Cognition Disorders/therapy , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Hippocampus/metabolism , Hippocampus/pathology , Humans , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptides/administration & dosage , Peptides/immunology , Phosphorylation/immunology , Serine/genetics , tau Proteins/genetics
11.
Neurobiol Dis ; 43(2): 486-94, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21569847

ABSTRACT

Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.


Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/therapy , Exercise Therapy/methods , Physical Conditioning, Animal/physiology , tau Proteins/genetics , Alzheimer Disease/physiopathology , Animals , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , tau Proteins/adverse effects , tau Proteins/antagonists & inhibitors
12.
Neurobiol Learn Mem ; 95(3): 296-304, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21167950

ABSTRACT

We evaluated various forms of hippocampus-dependent learning and memory, and hippocampal synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippocampus, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase in glial fibrillary acidic protein (GFAP) in hippocampus, but without signs of neuronal loss. These mice displayed spatial, social, and contextual learning and memory defects that could not be reduced to subtle neuromotor disability. The behavioral defects coincided with changes in hippocampal synaptic functioning and plasticity as measured in paired-pulse and novel long-term depression protocols. These results indicate that hippocampal tauopathy without neuronal cell loss can impair neural and behavioral plasticity, and further show that transgenic mice, such as the THY-Tau22 strain, might be useful for preclinical research on tauopathy pathogenesis and possible treatment.


Subject(s)
Association Learning/physiology , Hippocampus/physiopathology , Long-Term Synaptic Depression/physiology , Maze Learning/physiology , Tauopathies/physiopathology , Analysis of Variance , Animals , Conditioning, Classical/physiology , Disease Models, Animal , Fear , Food Preferences , Hippocampus/metabolism , Hippocampus/pathology , Humans , Immunohistochemistry , Male , Memory, Short-Term/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phosphorylation , Social Behavior , Tauopathies/metabolism , Tauopathies/pathology , tau Proteins/genetics , tau Proteins/metabolism
13.
Biochem Soc Trans ; 38(4): 967-72, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20658986

ABSTRACT

Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.


Subject(s)
Neurons/physiology , Protein Kinases/metabolism , Protein Multimerization/physiology , tau Proteins/metabolism , Animals , Cell Death/physiology , Chemical Precipitation , Disease Models, Animal , Humans , Models, Biological , Neurofibrillary Tangles/metabolism , Neurofibrillary Tangles/pathology , Neurons/metabolism , Neurons/pathology , Phosphorylation , Tauopathies/etiology , Tauopathies/metabolism , Tauopathies/pathology , tau Proteins/chemistry , tau Proteins/physiology
14.
Curr Alzheimer Res ; 6(2): 152-7, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19355850

ABSTRACT

Alzheimer's disease is a neurodegenerative disorder characterized by amyloid deposits and neurofibrillary tangles. Cholinergic dysfunction is also a main pathological feature of the disease. Nevertheless, the links between cholinergic dysfunction and neuropathological hallmarks of Alzheimer's are still unknown. In the present study, we aimed to further investigate Tau aggregation in cholinergic systems, in a Tau transgenic mouse model. THY-Tau22 mice have recently been described as a novel model of Alzheimer-like Tau pathology without motor deficits. This strain presents an age-dependent development of Tau pathology leading to synaptic dysfunctions as well as learning and memory impairments. In the present work, we observed that Tau pathology differentially affects cerebral structures. Interestingly, early Tau pathology was observed in both hippocampus and basal forebrain. Moreover, some morphological as well as functional alterations of the septohippocampal pathway suggest a disconnection between these two key brain regions in Alzheimer's disease. Finally, these data suggest that Tau pathology may participate in cholinergic degeneration.


Subject(s)
Alzheimer Disease/pathology , Hippocampus/pathology , Septum of Brain/pathology , tau Proteins/genetics , tau Proteins/metabolism , Age Factors , Animals , Brain Mapping , Disease Models, Animal , Glycine/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neural Pathways/pathology , Proline/genetics , Serine/genetics , Stilbamidines/metabolism , Valine/genetics
15.
Neurobiol Dis ; 20(2): 625-37, 2005 Nov.
Article in English | MEDLINE | ID: mdl-15936948

ABSTRACT

In Alzheimer's disease, the complex catabolism of amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta) peptide, the major component of amyloid deposits. APP is cleaved by beta- and alpha-secretases to generate APP carboxy-terminal fragments (CTFs). Abeta peptide and amyloid intracellular domain are resulting from the cleavage of APP-CTFs by the gamma-secretase. In the present study, we hypothesize that post-translational modification of APP-CTFs could modulate their processing by the gamma-secretase. Inhibition of the gamma-secretase was shown to increase the total amount of APP-CTFs. Moreover, we showed that this increase was more marked among the phosphorylated variants and directly related to the activity of the gamma-secretase, as shown by kinetics analyses. Phosphorylated CTFs were shown to associate to presenilin 1, a major protein of the gamma-secretase complex. The phosphorylation of CTFs at the threonine 668 resulting of the c-Jun N-terminal kinase activation was shown to enhance their degradation by the gamma-secretase. Altogether, our results demonstrated that phosphorylated CTFs can be the substrates of the gamma-secretase and that an increase in the phosphorylation of APP-CTFs facilitates their processing by gamma-secretase.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Brain/metabolism , Endopeptidases/metabolism , Peptide Fragments/metabolism , Alzheimer Disease/physiopathology , Amino Acid Sequence/physiology , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Protein Precursor/chemistry , Animals , Aspartic Acid Endopeptidases , Brain/physiopathology , Enzyme Inhibitors/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Membrane Proteins/metabolism , Peptide Fragments/chemistry , Phosphorylation , Presenilin-1 , Protein Processing, Post-Translational/physiology , Protein Structure, Tertiary/physiology , Rabbits , Threonine/metabolism , Tumor Cells, Cultured
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