Publications by authors named "Johannes Steffen"

15 Publications

  • Page 1 of 1

The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis.

Front Immunol 2021 21;12:619465. Epub 2021 Apr 21.

Institute of Inflammation and Neurodegeneration, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.

Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I/II-peptide complexes, which are required for the induction of T cell responses. The control of infection relies on Interferon-γ (IFNγ)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (β1i/LMP2, β2i/MECL-1 and β5i/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8 T cells were reduced in -infected TKO mice. Furthermore, impaired IFNγ, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 for the control of cerebral infection and subsequent neuroinflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.619465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099150PMC
April 2021

Autoantibody Formation and Mapping of Immunogenic Epitopes against Cold-Shock-Protein YB-1 in Cancer Patients and Healthy Controls.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Leipziger Str. 40, 39120 Magdeburg, Germany.

Cold shock Y-box binding protein-1 participates in cancer cell transformation and mediates invasive cell growth. It is unknown whether an autoimmune response against cancerous human YB-1 with posttranslational protein modifications or processing develops. We performed a systematic analysis for autoantibody formation directed against conformational and linear epitopes within the protein. Full-length and truncated recombinant proteins from prokaryotic and eukaryotic cells were generated. Characterization revealed a pattern of spontaneous protein cleavage, predominantly with the prokaryotic protein. Autoantibodies against prokaryotic, but not eukaryotic full-length and cleaved human YB-1 protein fragments were detected in both, healthy volunteers and cancer patients. A mapping of immunogenic epitopes performed with truncated -derived GST-hYB-1 proteins yielded distinct residues in the protein N- and C-terminus. A peptide array with consecutive overlapping 15mers revealed six distinct antigenic regions in cancer patients, however to a lesser extent in healthy controls. Finally, a protein cleavage assay was set up with recombinant pro- and eukaryotic-derived tagged hYB-1 proteins. A distinct cleavage pattern developed, that is retarded by sera from cancer patients. Taken together, a specific autoimmune response against hYB-1 protein develops in cancer patients with autoantibodies targeting linear epitopes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759818PMC
November 2020

Optogenetic and chemogenetic insights into the neurocircuitry of depression-like behaviour: A systematic review.

Eur J Neurosci 2021 Jan 11;53(1):9-38. Epub 2019 Nov 11.

Biological Psychology, TU Dresden, Dresden, Germany.

Major depressive disorder (MDD) and its treatment are challenges for global health. Optogenetics and chemogenetics are driving MDD research forward by unveiling causal relations between cell-type-specific control of neurons and depressive-like behaviour in rodents. Using a systematic search process, in this review, a set of 43 original studies applying optogenetic or chemogenetic techniques in rodent models of depression was identified. Our aim was to provide an examination of all available studies elucidating central neuronal mechanisms leading to depressive-like behaviour in rodents and thereby unveiling the most promising routes for future research. A complex interacting network of relevant structures, in which central circuitries causally related to depressive-like behaviour are implicated, has been identified. As most relevant structures emerge: medial prefrontal cortex, anterior cingulate cortex, amygdala, nucleus accumbens, ventral tegmental area, hippocampus and raphe nuclei. Further evidence, though examined by only few studies, emerges for structures like the lateral habenula, or medial dorsal thalamus. Most of the identified brain areas have previously been associated with MDD neuropathology, but now evidence can be provided for causal pathological mechanisms within a complex cortico-limbic reward circuitry. However, the studies also show conflicting results concerning the mechanisms underlying the causal involvement of specific circuitries. Comparability of studies is partly limited since even small deviations in methodological approaches lead to different outcomes. Factors influencing study outcomes were identified and need to be considered in future studies (e.g. frequency used for stimulation, time and duration of stimulation, limitations of applied animal models of MDD).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.14603DOI Listing
January 2021

Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner.

J Neuroinflammation 2019 Jul 29;16(1):159. Epub 2019 Jul 29.

Institute of Inflammation and Neurodegeneration, Medizinische Fakultät, Otto-von-Guericke-University Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany.

Background: It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes.

Methods: Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation.

Results: Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism.

Conclusion: Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1539-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661741PMC
July 2019

Combining convolutional neural networks and star convex cuts for fast whole spine vertebra segmentation in MRI.

Comput Methods Programs Biomed 2019 Aug 16;177:47-56. Epub 2019 May 16.

Department of Simulation and Graphics, University of Magdeburg Universitätsplatz 2, Magdeburg, 39106 Germany.

Background And Objective: We propose an automatic approach for fast vertebral body segmentation in three-dimensional magnetic resonance images of the whole spine. Previous works are limited to the lower thoracolumbar section and often take minutes to compute, which is problematic in clinical routine, for study data sets with numerous subjects or when the cervical or upper thoracic spine is to be analyzed.

Methods: We address these limitations by a novel graph cut formulation based on vertebra patches extracted along the spine. For each patch, our formulation incorporates appearance and shape information derived from a task-specific convolutional neural network as well as star-convexity constraints that ensure a topologically correct segmentation of each vertebra. When segmenting vertebrae individually, ambiguities will occur due to overlapping segmentations of adjacent vertebrae. We tackle this problem by novel non-overlap constraints between neighboring patches based on so-called encoding swaps. The latter allow us to obtain a globally optimal multi-label segmentation of all vertebrae in polynomial time.

Results: We validated our approach on two data sets. The first contains T- and T-weighted whole spine images of 64 subjects with varying health conditions. The second comprises 23 T-weighted thoracolumbar images of young healthy adults and is publicly available. Our method yielded Dice coefficients of 93.8  ±  2.6% and 96.0  ±  1.0% for both data sets with a run time of 1.35  ±  0.08 s and 0.90  ±  0.03 s per vertebra on consumer hardware. A complete whole spine segmentation took 32.4 ± 1.92 s on average.

Conclusions: Our results are superior to those of previous works at a fraction of their run time, which illustrates the efficiency and effectiveness of our whole spine segmentation approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmpb.2019.05.003DOI Listing
August 2019

Immunomodulatory Effects of the Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide in Acute .

Front Cell Infect Microbiol 2019 28;9:154. Epub 2019 May 28.

Medical Faculty, Institute of Inflammation and Neurodegeneration, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is an endogenous neuropeptide with distinct functions including the regulation of inflammatory processes. PACAP is able to modify the immune response by directly regulating macrophages and monocytes inhibiting the production of inflammatory cytokines, chemokines and free radicals. Here, we analyzed the effect of exogenous PACAP on peripheral immune cell subsets upon acute infection with the parasite . PACAP administration was followed by diminished innate immune cell recruitment to the peritoneal cavity of -infected mice. PACAP did not directly interfere with parasite replication, instead, indirectly reduced parasite burden in mononuclear cell populations by enhancing their phagocytic capacity. Although proinflammatory cytokine levels were attenuated in the periphery upon PACAP treatment, interleukin (IL)-10 and Transforming growth factor beta (TGF-β) remained stable. While PACAP modulated VPAC1 and VPAC2 receptors in immune cells upon binding, it also increased their expression of brain-derived neurotrophic factor (BDNF). In addition, the expression of p75 neurotrophin receptor (p75) on Ly6C inflammatory monocytes was diminished upon PACAP administration. Our findings highlight the immunomodulatory effect of PACAP on peripheral immune cell subsets during acute , providing new insights about host-pathogen interaction and the effects of neuropeptides during inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2019.00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546896PMC
January 2020

p75 regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection-induced neuroinflammation.

Glia 2019 01;67(1):193-211

Otto-von-Guericke University Magdeburg, Institute of Inflammation and Neurodegeneration, Medical Faculty, Magdeburg, Germany.

Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75 ) signaling. The p75 is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75 on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii (T. gondii) infection-induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75 upon infection in wild-type mice. Although cell recruitment and phagocytic capacity of p75 knockout (p75 ) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75 mice upregulated the production of the cytokines interleukin (IL)-10, IL-6 as well as IL-1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75 , were highly increased upon chronic infection in the brain of wild-type and p75 mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation-induced changes in spine density were rescued in the p75 mice. In conclusion, these findings indicate that neurotrophin signaling via the p75 affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/glia.23553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590406PMC
January 2019

Short-Term Effects of Microglia-Specific Mitochondrial Dysfunction on Amyloidosis in Transgenic Models of Alzheimer's Disease.

J Alzheimers Dis 2018 ;65(2):465-474

Department of Neurology, University of Rostock, Neurodegeneration Research Lab (NRL), Germany.

Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amyloid plaques, no difference was observed in either the amyloid level, total number, or microglial coverage of plaques. These results indicate that during this brief and early phase of amyloid deposition, beneficial mitochondrial alterations in the newly recruited third of microglial cells were not sufficient to affect the amyloidosis in APP-transgenic mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-180395DOI Listing
August 2019

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice.

Acta Neuropathol Commun 2017 06 20;5(1):49. Epub 2017 Jun 20.

Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) / Oslo Universiy Hospital (OUS), Postboks 4950 Nydalen, Oslo, 0424, Norway.

Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer's disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-017-0448-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480119PMC
June 2017

Revisiting rodent models: Octodon degus as Alzheimer's disease model?

Acta Neuropathol Commun 2016 08 26;4(1):91. Epub 2016 Aug 26.

University of Lübeck (UzL), LIED, Lübeck, Germany.

Alzheimer's disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these 'engineered' models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural 'sporadic Alzheimer's disease model' with 'Alzheimer's disease-like neuropathology'. To unveil advantages over the 'artificial' mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer's disease patients or transgenic disease models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-016-0363-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002178PMC
August 2016

Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies.

Mol Neurobiol 2016 09 29;53(7):4728-44. Epub 2015 Aug 29.

Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway.

Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNA(Arg) genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-015-9399-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965489PMC
September 2016

Ultrasound texture-based CAD system for detecting neuromuscular diseases.

Int J Comput Assist Radiol Surg 2015 Sep 2;10(9):1493-503. Epub 2014 Dec 2.

Department of Simulation and Graphics, Otto von Guericke University, Universitätsplatz 2, 39106, Magdeburg, Germany,

Purpose: Diagnosis of neuromuscular diseases in ultrasonography is a challenging task since experts are often unable to discriminate between healthy and pathological cases. A computer-aided diagnosis (CAD) system for skeletal muscle ultrasonography was developed and tested for myositis detection in ultrasound images of biceps brachii.

Methods: Several types of features were extracted from rectangular and polygonal image regions-of-interest (ROIs), including first-order statistics, wavelet-based features, and Haralick's features. Features were chosen that are sensitive to the change in contrast and structure for pathological ultrasound images of neuromuscular diseases. The number of features was reduced by applying different sequential feature selection strategies followed by a supervised principal component analysis. For classification, two linear approaches were investigated: Fisher's classifier and the linear support vector machine (SVM) as well as the nonlinear [Formula: see text]-nearest neighbor approach. The CAD system was benchmarked on datasets of 18 subjects, seven of which were healthy, while 11 were affected by myositis. Three expert radiologists provided pre-classification and testing interpretations.

Results: Leave-one-out cross-validation on the training data revealed that the linear SVM was best suited for discriminating healthy and pathological muscle tissue, achieving 85/87 % accuracy, 90 % sensitivity, and 83/85 % specificity, depending on the radiologist.

Conclusion: A muscle ultrasonography CAD system was developed, allowing a classification of an ultrasound image by one-click positioning of rectangular ROIs with minimal user effort. The applicability of the system was demonstrated with the challenging example of myositis detection, showing highly accurate results that were robust to imprecise user input.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11548-014-1133-6DOI Listing
September 2015

Genomic background-related activation of microglia and reduced β-amyloidosis in a mouse model of Alzheimer's disease.

Eur J Microbiol Immunol (Bp) 2013 Mar;3(1):21-27

Neurodegeneration Research Lab (NRL), Department of Neurology, University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.

Alzheimer's disease (AD) is by far the most common neurodegenerative disease. AD is histologically characterized not only by extracellular senile plaques and vascular deposits consisting of β-amyloid (Aβ) but also by accompanying neuroinflammatory processes involving the brain's microglia. The importance of the microglia is still in controversial discussion, which currently favors a protective function in disease progression. Recent findings by different research groups highlighted the importance of strain-specific and mitochondria-specific genomic variations in mouse models of cerebral β-amyloidosis. Here, we want to summarize our previously presented data and add new results that draw attention towards the consideration of strain-specific genomic alterations in the setting of APP transgenes. We present data from APP-transgenic mice in commonly used C57Bl/6J and FVB/N genomic backgrounds and show a direct influence on the kinetics of Aβ deposition and the activity of resident microglia. Plaque size, plaque deposition rate and the total amount of Aβ are highest in C57Bl/6J mice as compared to the FVB/N genomic background, which can be explained at least partially by a reduced microglia activity towards amyloid deposits in the C57BL/6J strain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1556/EuJMI.3.2013.1.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694725PMC
March 2013

ABC transporters B1, C1 and G2 differentially regulate neuroregeneration in mice.

PLoS One 2012 24;7(4):e35613. Epub 2012 Apr 24.

Neurodegeneration Research Laboratory (NRL), Department of Neurology, Universities of Rostock and Magdeburg, Magdeburg, Germany.

Background: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1).

Methodology And Principal Findings: Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB1(0/0)) as evidenced by lowered numbers of doublecortin(+) (-36%) and calretinin(+) (-37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1(0/0) and ABCC1(0/0) mice, whereas ABCG2(0/0) mice were mostly unaffected.

Conclusion And Significance: Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035613PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335815PMC
August 2012

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.

J Clin Invest 2011 Oct 1;121(10):3924-31. Epub 2011 Sep 1.

Department of Neurology, Neurodegeneration Research Laboratory, University of Rostock, Rostock, Germany.

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI57867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195473PMC
October 2011