2024-03-28T11:13:29Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/3260722019-08-30T11:35:39Zcom_10033_620722col_10033_620723NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.Heneka, Michael TKummer, Markus PStutz, AndreaDelekate, AndreaSchwartz, StephanieVieira-Saecker, AnaGriep, AngelikaAxt, DaisyRemus, AnitaTzeng, Te-ChenGelpi, EllenHalle, AnnettKorte, MartinLatz, EickeGolenbock, Douglas TAlzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.2014-09-122014-09-122013-01-31ArticleNLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Nature1476-46872325493010.1038/nature11729http://hdl.handle.net/10033/326072NatureenArchived with thanks to Natureoai:repository.helmholtz-hzi.de:10033/5839082019-08-30T11:33:02Zcom_10033_620722col_10033_620723Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse HippocampusMonory, K.Polack, M.Remus, A.Lutz, B.Korte, M.Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.2015-12-152015-12-152015-03-04ArticleCannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus 2015, 35 (9):3842 Journal of Neuroscience0270-64741529-240110.1523/JNEUROSCI.3167-14.2015http://hdl.handle.net/10033/583908Journal of Neurosciencehttp://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.3167-14.2015oai:repository.helmholtz-hzi.de:10033/6154952019-08-30T11:30:58Zcom_10033_620722col_10033_620723The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.Klevanski, MajaHerrmann, UlrikeWeyer, Sascha WFol, RomainCartier, NathalieWolfer, David PCaldwell, John HKorte, MartinMüller, Ulrike CHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies.2016-07-052016-07-052015-12-09ArticleThe APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. 2015, 35 (49):16018-33 J. Neurosci.1529-24012665885610.1523/JNEUROSCI.2009-15.2015http://hdl.handle.net/10033/615495The Journal of neuroscience : the official journal of the Society for Neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6156512019-08-30T11:30:58Zcom_10033_620722col_10033_620723Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth.Chen, Jian-HuaKellner, YvesZagrebelsky, MartaGrunwald, MatthiasKorte, MartinWalla, Peter JomoHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.Two-photon fluorescence correlation spectroscopy (2P-FCS) within single dendritic spines of living hippocampal pyramidal neurons was used to resolve various subpopulations of mobile F-actin during activity-dependent structural changes such as potentiation induced spine head growth. Two major classes of mobile F-actin were discovered: very dynamic and about a hundred times less dynamic F-actin. Spine head enlargement upon application of Tetraethylammonium (TEA), a protocol previously used for the chemical induction of long-term potentiation (cLTP) strictly correlated to changes in the dynamics and filament numbers in the different actin filament fractions. Our observations suggest that spine enlargement is governed by a mechanism in which longer filaments are first cut into smaller filaments that cooperate with the second, increasingly dynamic shorter actin filament population to quickly reorganize and expand the actin cytoskeleton within the spine head. This process would allow a fast and efficient spine head enlargement using a major fraction of the actin filament population that was already present before spine head growth.2016-07-072016-07-072015ArticleTwo-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth. 2015, 10 (5):e0128241 PLoS ONE1932-62032602092710.1371/journal.pone.0128241http://hdl.handle.net/10033/615651PloS oneenhttp://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6210752019-08-30T11:37:24Zcom_10033_620722col_10033_620723Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity.Ludewig, SusannKorte, MartinHemholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.The amyloid precursor protein (APP) is well known to be involved in the pathophysiology of Alzheimer's disease (AD) via its cleavage product amyloid ß (Aß). However, the physiological role of APP, its various proteolytic products and the amyloid precursor-like proteins 1 and 2 (APLP1/2) are still not fully clarified. Interestingly, it has been shown that learning and memory processes represented by functional and structural changes at synapses are altered in different APP and APLP1/2 mouse mutants. In addition, APP and its fragments are implicated in regulating synaptic strength further reinforcing their modulatory role at the synapse. While APLP2 and APP are functionally redundant, the exclusively CNS expressed APLP1, might have individual roles within the synaptic network. The proteolytic product of non-amyloidogenic APP processing, APPsα, emerged as a neurotrophic peptide that facilitates long-term potentiation (LTP) and restores impairments occurring with age. Interestingly, the newly discovered η-secretase cleavage product, An-α acts in the opposite direction, namely decreasing LTP. In this review we summarize recent findings with emphasis on the physiological role of the APP gene family and its proteolytic products on synaptic function and plasticity, especially during processes of hippocampal LTP. Therefore, we focus on literature that provide electrophysiological data by using different mutant mouse strains either lacking full-length or parts of the APP proteins or that utilized secretase inhibitors as well as secreted APP fragments.2017-08-232017-08-232016ArticleNovel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity. 2016, 9:161 Front Mol Neurosci1662-50992816367310.3389/fnmol.2016.00161http://hdl.handle.net/10033/621075Frontiers in molecular neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6211982019-08-30T11:30:58Zcom_10033_620722col_10033_620723Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease.Li, QinNavakkode, SheejaRothkegel, MartinSoong, Tuck WahSajikumar, SreedharanKorte, MartinHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.2017-12-082017-12-082017-05-23ArticleMetaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease. 2017, 114 (21):5527-5532 Proc. Natl. Acad. Sci. U.S.A.1091-64902848401210.1073/pnas.1613700114http://hdl.handle.net/10033/621198Proceedings of the National Academy of Sciences of the United States of AmericaPMC5448214enhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448214/http://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6212092019-08-30T11:28:51Zcom_10033_620722col_10033_620723APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission.Schilling, SandraMehr, AnnikaLudewig, SusannStephan, JonathanZimmermann, MariusAugust, AlexanderStrecker, PaulKorte, MartinKoo, Edward HMüller, Ulrike CKins, StefanEggert, SimoneHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAMs) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both the secreted APP ectodomain that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologs of APP exist in mammals: the APP like proteins APLP1 and APLP2, exhibiting functions that partly overlap with those of APP. Here we tested whether APLP1 and APLP2 also show features of SAMs. We found that all three family members were upregulated during postnatal development coinciding with synaptogenesis. We observed presynaptic and postsynaptic localization of all APP family members and could show that heterologous expression of APLP1 or APLP2 in non-neuronal cells induces presynaptic differentiation in contacting axons of cocultured neurons, similar to APP and other SAMs. Moreover, APP/APLPs all bind to synaptic-signaling molecules, such as MINT/X11. Furthermore, we report that aged APLP1 knock-out mice show impaired basal transmission and a reduced mEPSC frequency, likely resulting from reduced spine density. This demonstrates an essential nonredundant function of APLP1 at the synapse. Compared to APP, APLP1 exhibits increased trans-cellular binding and elevated cell-surface levels due to reduced endocytosis. In conclusion, our results establish that APLPs show typical features of SAMs and indicate that increased surface expression, as observed for APLP1, is essential for proper synapse formation in vitro and synapse maintenance in vivoSIGNIFICANCE STATEMENT According to the amyloid-cascade hypothesis, Alzheimer's disease is caused by the accumulation of Aβ peptides derived from sequential cleavage of the amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Here we show that all mammalian APP family members (APP, APLP1, and APLP2) exhibit synaptogenic activity, involving trans-synaptic dimerization, similar to other synaptic cell adhesion molecules, such as Neuroligin/Neurexin. Importantly, our study revealed that the loss of APLP1, which is one of the major substrates of BACE1, causes reduced spine density in aged mice. Because some therapeutic interventions target APP processing (e.g., BACE inhibitors), those strategies may alter APP/APLP physiological function. This should be taken into account for the development of pharmaceutical treatments of Alzheimer's disease.2017-12-182017-12-182017-05-24ArticleAPLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission. 2017, 37 (21):5345-5365 J. Neurosci.1529-24012845054010.1523/JNEUROSCI.1875-16.2017http://hdl.handle.net/10033/621209The Journal of neuroscience : the official journal of the Society for Neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6213572019-08-30T11:34:22Zcom_10033_620722col_10033_620723Imbalance of synaptic actin dynamics as a key to fragile X syndrome?Michaelsen-Preusse, KristinFeuge, JonasKorte, MartinHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.Our experiences and memories define who we are, and evidence has accumulated that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses show a strong structure-to-function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders such as fragile X syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X-linked fragile X mental retardation 1 gene and loss of its gene product, the RNA-binding protein fragile X mental retardation protein 1 (FMRP), which normally can be found both pre- and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse, and although hundreds of FMRP-target mRNAs could be identified only a very few interactions between FMRP and actin-regulating proteins have been reported and validated. In this review we give an overview of recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.2018-04-182018-04-182018-01-30ArticleImbalance of synaptic actin dynamics as a key to fragile X syndrome? 2018 J. Physiol. (Lond.)1469-77932938037710.1113/JP275571http://hdl.handle.net/10033/621357The Journal of physiologyenhttp://creativecommons.org/licenses/by-nc-sa/4.0/oai:repository.helmholtz-hzi.de:10033/6214052019-08-30T11:28:46Zcom_10033_620722col_10033_620723A guiding map for inflammation.Netea, Mihai GBalkwill, FrancesChonchol, MichelCominelli, FabioDonath, Marc YGiamarellos-Bourboulis, Evangelos JGolenbock, DouglasGresnigt, Mark SHeneka, Michael THoffman, Hal MHotchkiss, RichardJoosten, Leo A BKastner, Daniel LKorte, MartinLatz, EickeLibby, PeterMandrup-Poulsen, ThomasMantovani, AlbertoMills, Kingston H GNowak, Kristen LO'Neill, Luke APickkers, Petervan der Poll, TomRidker, Paul MSchalkwijk, JoostSchwartz, David ASiegmund, BrittaSteer, Clifford JTilg, Herbertvan der Meer, Jos W Mvan de Veerdonk, Frank LDinarello, Charles AHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.2018-06-212018-06-212017-07-19Article1529-29162872272010.1038/ni.3790http://hdl.handle.net/10033/621405http://creativecommons.org/licenses/by-nc-sa/3.0/us/Attribution-NonCommercial-ShareAlike 3.0 United Statesoai:repository.helmholtz-hzi.de:10033/6216222019-08-30T11:33:01Zcom_10033_620722col_10033_620723Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus.Zimmermann, TinaMaroso, MattiaBeer, AnnikaBaddenhausen, SarahLudewig, SusannFan, WenqiangVennin, ConstanceLoch, SebastianBerninger, BenediktHofmann, ClementineKorte, MartinSoltesz, IvanLutz, BeatLeschik, JuliaHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.2018-12-192018-12-192018-10-11Article1460-21993030749110.1093/cercor/bhy258http://hdl.handle.net/10033/621622PMC6215469http://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalOxford University Publishingoai:repository.helmholtz-hzi.de:10033/6216282019-08-30T11:30:28Zcom_10033_620722col_10033_620723The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology.Martinez Hernandez, AnaUrbanke, HendrikGillman, Alan LLee, JoonRyazanov, SergeyAgbemenyah, Hope YBenito, EvaJain, GauravKaurani, LalitGrigorian, GayaneLeonov, AndreiRezaei-Ghaleh, NasrollahWilken, PetraArce, Fernando TeranWagner, JensFuhrmann, MartinCaruana, MarioCamilleri, AngeliqueVassallo, NevilleZweckstetter, MarkusBenz, RolandGiese, ArminSchneider, AnjaKorte, MartinLal, RatneshGriesinger, ChristianEichele, GregorFischer, AndreAlzheimer's diseaseAβ channelsamyloid pathologygene expressionmembrane poresAlzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further.2019-01-032019-01-032018-01-01Article1757-46842920863810.15252/emmm.201707825http://hdl.handle.net/10033/621628enhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 Internationaloai:repository.helmholtz-hzi.de:10033/6217262019-08-30T11:32:16Zcom_10033_620722col_10033_620723Immune Challenge Alters Reactivity of Hippocampal Noradrenergic System in Prenatally Stressed Aged Mice.Grigoryan, GayaneLonnemann, NiklasKorte, MartinHZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.Prenatal stress (PS) has long-term sequelae for the morphological and functional status of the central nervous system of the progeny. A PS-induced proinflammatory status of the organism may result in an impairment of both hippocampal synaptic plasticity and hippocampus-dependent memory formation in adults. We addressed here the question of how PS-induced alterations in the immune response in young and old mice may contribute to changes in hippocampal function in aging. Immune stimulation (via2019-03-192019-03-192019-01-01ArticleNeural Plast. 2019 Jan 21;2019:3152129. doi: 10.1155/2019/3152129. eCollection 2019.1687-54433080499010.1155/2019/3152129http://hdl.handle.net/10033/621726Neural plasticityenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalHindawioai:repository.helmholtz-hzi.de:10033/6217942019-08-30T11:33:00Zcom_10033_620722col_10033_620723Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.Namikawa, KazuhikoDorigo, AlessandroZagrebelsky, MartaRusso, GiulioKirmann, ToniFahr, WielandDübel, StefanKorte, MartinKöster, Reinhard WHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Purkinje cellsbioimagingcerebellumneuronal degenerationspinocerebellar ataxiazebrafishPurkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENT SCA13 patients carrying a KCNC3R420H allele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseases in vivo from the molecular to the behavioral level.2019-06-032019-06-032019-05-15ArticleJ Neurosci. 2019 May 15;39(20):3948-3969. doi: 10.1523/JNEUROSCI.1862-18.2019. Epub 2019 Mar 12.1529-24013086266610.1523/JNEUROSCI.1862-18.2019http://hdl.handle.net/10033/621794The journal of neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalSociety of Neuroscienceoai:repository.helmholtz-hzi.de:10033/6220072019-11-07T01:59:59Zcom_10033_620722col_10033_620723Fast Regulation of GABAR Diffusion Dynamics by Nogo-A Signaling.Fricke, SteffenMetzdorf, KristinOhm, MelanieHaak, StefanHeine, MartinKorte, MartinZagrebelsky, MartaHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.EI balanceGABAARsNogo-AS1PR2calcineurinexcitationinhibitionquantum dotssingle particle trackingsynaptic plasticityPrecisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.2019-11-062019-11-062019-10-15ArticleCell Rep. 2019 Oct 15;29(3):671-684.e6. doi: 10.1016/j.celrep.2019.09.015.2211-12473161863510.1016/j.celrep.2019.09.015http://hdl.handle.net/10033/622007Cell Reportsenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalElsevieroai:repository.helmholtz-hzi.de:10033/6220612020-01-04T02:01:22Zcom_10033_620722col_10033_620723Amyloid, APP, and Electrical Activity of the Brain.Hefter, DimitriLudewig, SusannDraguhn, AndreasKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.APPAlzheimer’s diseaseamyloidoscillationsplasticitysynaptic transmissionThe Amyloid Precursor Protein (APP) is infamous for its proposed pivotal role in the pathogenesis of Alzheimer’s disease (AD). Much research on APP focusses on potential contributions to neurodegeneration, mostly based on mouse models with altered expression or mutated forms of APP. However, cumulative evidence from recent years indicates the indispensability of APP and its metabolites for normal brain physiology. APP contributes to the regulation of synaptic transmission, plasticity, and calcium homeostasis. It plays an important role during development and it exerts neuroprotective effects. Of particular importance is the soluble secreted fragment APPsα which mediates many of its physiological actions, often counteracting the effects of the small APP-derived peptide Aβ. Understanding the contribution of APP for normal functions of the nervous system is of high importance, both from a basic science perspective and also as a basis for generating new pathophysiological concepts and therapeutic approaches in AD. In this article, we review the physiological functions of APP and its metabolites, focusing on synaptic transmission, plasticity, calcium signaling, and neuronal network activity.2020-01-032020-01-032019-11-29ArticleNeuroscientist. 2019 Nov 29:1073858419882619. doi: 10.1177/1073858419882619.1089-40983177951810.1177/1073858419882619http://hdl.handle.net/10033/622061The neuroscientistenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalSage Publikationsoai:repository.helmholtz-hzi.de:10033/6222852020-06-10T01:29:38Zcom_10033_620722com_10033_620601col_10033_620723col_10033_620602Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS.Hosseini, ShirinMichaelsen-Preusse, KristinGrigoryan, GayaneChhatbar, ChintanKalinke, UlrichKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-β-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-β has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-β treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade.2020-06-092020-06-09ArticleCell Rep. 2020;31(7):107666. doi:10.1016/j.celrep.2020.107666.3243397510.1016/j.celrep.2020.107666http://hdl.handle.net/10033/6222852211-1247Cell reportsenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalElsevier (Cell Press)oai:repository.helmholtz-hzi.de:10033/6223122020-06-26T02:39:38Zcom_10033_620722com_10033_620626com_10033_620636col_10033_620723col_10033_620627col_10033_620638Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function.Hosseini, ShirinWilk, EstherMichaelsen-Preusse, KristinGerhauser, IngoBaumgärtner, WolfgangGeffers, RobertSchughart, KlausKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.dendritic spineshippocampusinfluenzamicroglianeuroinflammationstructural plasticityAcute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.2020-06-252020-06-252018-02-27ArticleOther. J Neurosci. 2018;38(12):3060-3080. doi:10.1523/JNEUROSCI.1740-17.2018.2948712410.1523/JNEUROSCI.1740-17.2018http://hdl.handle.net/10033/6223121529-2401The Journal of neuroscience : the official journal of the Society for Neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalSociety for Neuroscienceoai:repository.helmholtz-hzi.de:10033/6223522020-07-16T02:29:01Zcom_10033_620722col_10033_620723BDNF signaling during the lifetime of dendritic spines.Zagrebelsky, MartaTacke, CharlotteKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Brain-derived neurotrophic factorDendritic spinesNeurotrophinTrkBp75NTRDendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.2020-07-152020-07-152020-06-14ArticleOtherCell Tissue Res. 2020;10.1007/s00441-020-03226-5. doi:10.1007/s00441-020-03226-5.3253772410.1007/s00441-020-03226-5http://hdl.handle.net/10033/6223521432-0878Cell and tissue researchenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalSringer Natureoai:repository.helmholtz-hzi.de:10033/6223752020-08-04T02:35:17Zcom_10033_620722col_10033_620723Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent.Beyer, Marianna M SLonnemann, NiklasRemus, AnitaLatz, EickeHeneka, Michael TKorte, MartinAPP/PS1LPSNLRP3hippocampusneuroinflammationsepsisNeuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli, which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype.SIGNIFICANCE STATEMENT Acute peripheral immune stimulation has been shown to have both positive and negative effects on Aβ deposition. Improvements or worsening may be possible in acute inflammation. However, there is still no evidence of effects longer than a month after stimulation. The data are pointing to an important role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome for mediating the long-term consequences of systemic immune stimulation, which in addition turns out to be age dependent.2020-08-032020-08-032020-06-04ArticleJ Neurosci. 2020;40(28):5480-5494. doi:10.1523/JNEUROSCI.0200-20.2020.3249937910.1523/JNEUROSCI.0200-20.2020http://hdl.handle.net/10033/6223751529-2401The Journal of neuroscience : the official journal of the Society for Neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalSociety for Neuroscienceoai:repository.helmholtz-hzi.de:10033/6225202021-07-06T11:57:20Zcom_10033_620722com_10033_622921col_10033_622925col_10033_620723Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs.Cornelius, Angela D AHosseini, ShirinSchreier, SarahFritzsch, DavidWeichert, LoreenMichaelsen-Preusse, KristinFendt, MarkusKröger, AndreaTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.HippocampusInapparent infectionLangat virusLearning and memoryTick-borne encephalitis virusType I interferonTo compare the effect of low and high viral replication in the brain, wildtype and Irf-7-/- mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed.2020-10-192020-10-192020-09-20ArticleNeuroinflammation. 2020 Sep 20;17(1):278. doi: 10.1186/s12974-020-01951-w.3295160210.1186/s12974-020-01951-whttp://hdl.handle.net/10033/6225201742-2094Journal of neuroinflammationenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalBioMed Centraloai:repository.helmholtz-hzi.de:10033/6225952020-11-19T05:37:23Zcom_10033_620722col_10033_620723The impact of the digital revolution on human brain and behavior: where do we stand? .Korte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.addictionadolescenceamygdalaattentionbrain developmentcognitive neurosciencedigital medialanguage developmentprefrontal cortexThis overview will outline the current results of neuroscience research on the possible effects of digital media use on the human brain, cognition, and behavior. This is of importance due to the significant amount of time that individuals spend using digital media. Despite several positive aspects of digital media, which include the capability to effortlessly communicate with peers, even over a long distance, and their being used as training tools for students and the elderly, detrimental effects on our brains and minds have also been suggested. Neurological consequences have been observed related to internet/gaming addiction, language development, and processing of emotional signals. However, given that much of the neuroscientific research conducted up to now relies solely on self-reported parameters to assess social media usage, it is argued that neuroscientists need to include datasets with higher precision in terms of what is done on screens, for how long, and at what age.2020-11-182020-11-18ArticleDialogues Clin Neurosci. 2020 Jun;22(2):101-111. doi: 10.31887/DCNS.2020.22.2/mkorte.3269951010.31887/DCNS.2020.22.2/mkortehttp://hdl.handle.net/10033/6225951958-5969Dialogues in clinical neuroscienceenhttp://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 InternationalLaboratoires Servieroai:repository.helmholtz-hzi.de:10033/6226692021-01-09T01:46:02Zcom_10033_620722col_10033_620723The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer's disease.Lonnemann, NiklasHosseini, ShirinMarchetti, CarloSkouras, Damaris BStefanoni, DavideD'Alessandro, AngeloDinarello, Charles AKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Alzheimer’s disease synapticcognitive functionsynaptic plasticityNumerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.2021-01-082021-01-082020-11-30ArticleProc Natl Acad Sci U S A. 2020 Dec 15;117(50):32145-32154. doi: 10.1073/pnas.2009680117. Epub 2020 Nov 30.3325757610.1073/pnas.2009680117http://hdl.handle.net/10033/6226691091-6490Proceedings of the National Academy of Sciences of the United States of Americaenhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 InternationalNational Academy of Sciencesoai:repository.helmholtz-hzi.de:10033/6228172021-04-02T01:38:20Zcom_10033_620722col_10033_620723Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology.Patnaik, AbhisarikaZagrebelsky, MartaKorte, MartinHolz, AndreasHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Synapse and dendritic spine loss induced by amyloid-β oligomers is one of the main hallmarks of the early phases of Alzheimer's disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75NTR) binds amyloid-β oligomers in the nM range. While it was shown that µM concentrations of amyloid-β mediate cell death, the role and intracellular signaling of p75NTR for dendritic spine pathology induced by sublethal concentrations of amyloid-β has not been analyzed. We describe here p75NTR as a crucial binding partner in mediating effects of soluble amyloid-β oligomers on dendritic spine density and structure in non-apoptotic hippocampal neurons. Removing or over-expressing p75NTR in neurons rescues or exacerbates the typical loss of dendritic spines and their structural alterations observed upon treatment with nM concentrations of amyloid-β oligomers. Moreover, we show that binding of amyloid-β oligomers to p75NTR activates the RhoA/ROCK signaling cascade resulting in the fast stabilization of the actin spinoskeleton. Our results describe a role for p75NTR and downstream signaling events triggered by binding of amyloid-β oligomers and causing dendritic spine pathology. These observations further our understanding of the molecular mechanisms underlying one of the main early neuropathological hallmarks of AD.2021-04-012021-04-012020-08-07ArticleSci Rep. 2020 Aug 7;10(1):13322. doi: 10.1038/s41598-020-70153-4.3277007010.1038/s41598-020-70153-4http://hdl.handle.net/10033/6228172045-2322Scientific reportsenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalNPGoai:repository.helmholtz-hzi.de:10033/6229002021-06-12T01:45:53Zcom_10033_620722col_10033_620723Respiratory viral infections and associated neurological manifestationsHosseini, ShirinMichaelsen-Preusse, KristinKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.NeurologyClinical Neurologycentral nervous systemcoronavirusinfluenza virusneurodegenerationrespiratory viral infectionsRespiratory viruses as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target tissue of these viruses is the lung, they can induce immediate or delayed neuropathological manifestations in humans and animals. Already after the Spanish flu (1918/20) evidence accumulated that neurological diseases can be induced by respiratory viral infections as some patients showed parkinsonism, seizures, or dementia. In the recent outbreak of COVID-19 as well patients suffered from headache, dizziness, nausea, or reduced sense of smell and taste suggesting that SARS-CoV2 may affect the central nervous system (CNS). It was shown that different respiratory viral infections can lead to deleterious complications in the CNS by a direct invasion of the virus into the brain and/or indirect pathways via proinflammatory cytokine expression. Therefore, we will discuss in this review mechanisms how the most prevalent respiratory viruses including influenza and coronaviruses in humans can exert long-lasting detrimental effects on the CNS and possible links to the development of neurodegenerative diseases as an enduring consequence.2021-06-112021-06-112021-03-29ReviewNeuroforum, 27, (2), 2021, pp. 53-65. https://doi.org/10.1515/nf-2020-00350947-087510.1515/nf-2020-0035http://hdl.handle.net/10033/6229002363-7013Neuroforum10.1515/nf-2020-0035enhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalWalter de Gruyter GmbHoai:repository.helmholtz-hzi.de:10033/6230472021-09-28T01:47:56Zcom_10033_620722com_10033_620626col_10033_620723col_10033_620627Long-Term Consequence of Non-neurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer's Disease Symptoms.Hosseini, ShirinMichaelsen-Preusse, KristinSchughart, KlausKorte, MartinHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Alzheimer’s diseasebehaviorhippocampusinfluenza virusmicrogliasynaptic plasticityInfluenza viruses until today are a leading cause of worldwide severe pandemics and represent a major threat to human and animal health. Although the primary target of influenza viruses is the lung, infection may manifest with acute and even chronic neurological complications (e.g., status epilepticus, encephalopathies, and encephalitis) potentially increasing the long-term risk for neurodegenerative diseases. We previously described that a peripheral influenza A virus (IAV) infection caused by non-neurotropic H3N2 (maHK68) variant leads to long-term neuroinflammation and synapse loss together with impaired memory formation in young adult mice. Processes of neuroinflammation have been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and prolonged or excessive innate immune responses are considered a risk factor for AD. Here, the role of purely peripheral IAV infection for the development and progression of AD in a transgenic mouse model (APP/PS1) was investigated. At 2 months of age, mice were infected with H3N2 IAV and the detailed analysis of microglia morphology revealed neuroinflammation in the hippocampus already of 6 months old non-infected APP/PS1 mice together with impaired spatial learning, however, microglia activation, amyloid-β plaques load and cognitive impairments were even more pronounced in APP/PS1 mice upon H3N2 infection. Moreover, CA1 hippocampal dendritic spine density was reduced even at 120 dpi compared to wild-type and also to non-infected APP/PS1 mice, whereas neuronal cells number was not altered. These findings demonstrate that non-neurotropic H3N2 IAV infection as a peripheral immune stimulation may exacerbate AD symptoms possibly by triggering microglial hyperactivation.2021-09-272021-09-272021-04-28ArticleFront Cell Neurosci. 2021 Apr 28;15:643650. doi: 10.3389/fncel.2021.643650.1662-51023399494610.3389/fncel.2021.643650http://hdl.handle.net/10033/623047Frontiers in cellular neuroscienceenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalFrontiersoai:repository.helmholtz-hzi.de:10033/6230512021-09-29T01:53:03Zcom_10033_620722col_10033_620723Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism-like phenotype.Steubler, VickyErdinger, SusanneBack, Michaela KLudewig, SusannFässler, DominiqueRichter, MaxHan, KangSlomianka, LutzAmrein, Irmgardvon Engelhardt, JakobWolfer, David PKorte, MartinMüller, Ulrike CHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.AlzheimerAmyloid precursor proteinAutism spectrum disorderlearning and memorysynaptic plasticityThe key role of APP for Alzheimer pathogenesis is well established. However, perinatal lethality of germline knockout mice lacking the entire APP family has so far precluded the analysis of its physiological functions for the developing and adult brain. Here, we generated conditional APP/APLP1/APLP2 triple KO (cTKO) mice lacking the APP family in excitatory forebrain neurons from embryonic day 11.5 onwards. NexCre cTKO mice showed altered brain morphology with agenesis of the corpus callosum and disrupted hippocampal lamination. Further, NexCre cTKOs revealed reduced basal synaptic transmission and drastically reduced long-term potentiation that was associated with reduced dendritic length and reduced spine density of pyramidal cells. With regard to behavior, lack of the APP family leads not only to severe impairments in a panel of tests for learning and memory, but also to an autism-like phenotype including repetitive rearing and climbing, impaired social communication, and deficits in social interaction. Together, our study identifies essential functions of the APP family during development, for normal hippocampal function and circuits important for learning and social behavior.2021-09-282021-09-282021-05-19ArticleEMBO J. 2021 Jun 15;40(12):e107471. doi: 10.15252/embj.2020107471. Epub 2021 May 19.3400886210.15252/embj.2020107471http://hdl.handle.net/10033/6230511460-2075The EMBO journalenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalWiley/EMBO Pressoai:repository.helmholtz-hzi.de:10033/6230942021-11-26T16:55:42Zcom_10033_620722col_10033_620723Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling.Petkova-Tuffy, AndoniaGödecke, NinaViotti, JulioKorte, MartinDresbach, ThomasHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Neuroligin-1,Brain-derived neurotrophic factorPresynaptic maturationBackground: Maturation is a process that allows synapses to acquire full functionality, optimizing their activity to diverse neural circuits, and defects in synaptic maturation may contribute to neurodevelopmental disorders. Neuroligin-1 (NL1) is a postsynaptic cell adhesion molecule essential for synapse maturation, a role typically attributed to binding to pre-synaptic ligands, the neurexins. However, the pathways underlying the action of NL1 in synaptic maturation are incompletely understood, and some of its previously observed effects seem reminiscent of those described for the neurotrophin brain-derived neurotrophic factor (BDNF). Here, we show that maturational increases in active zone stability and synaptic vesicle recycling rely on the joint action of NL1 and brain-derived neurotrophic factor (BDNF).
Results: Applying BDNF to hippocampal neurons in primary cultures or organotypical slice cultures mimicked the effects of overexpressing NL1 on both structural and functional maturation. Overexpressing a NL1 mutant deficient in neurexin binding still induced presynaptic maturation. Like NL1, BDNF increased synaptic vesicle recycling and the augmentation of transmitter release by phorbol esters, both hallmarks of presynaptic maturation. Mimicking the effects of NL1, BDNF also increased the half-life of the active zone marker bassoon at synapses, reflecting increased active zone stability. Overexpressing NL1 increased the expression and synaptic accumulation of BDNF. Inhibiting BDNF signaling pharmacologically or genetically prevented the effects of NL1 on presynaptic maturation. Applying BDNF to NL1-knockout mouse cultures rescued defective presynaptic maturation, indicating that BDNF acts downstream of NL1 and can restore presynaptic maturation at late stages of network development.
Conclusions: Our data introduce BDNF as a novel and essential component in a transsynaptic pathway linking NL1-mediated cell adhesion, neurotrophin action, and presynaptic maturation. Our findings connect synaptic cell adhesion and neurotrophin signaling and may provide a therapeutic approach to neurodevelopmental disorders by targeting synapse maturation.2021-11-112021-11-112021-09-27ArticleJ Biol Chem. 2021 Oct 9;297(5):101298. doi: 10.1016/j.jbc.2021.101298. Epub ahead of print. PMID: 34637789.3457972010.1186/s12915-021-01145-7http://hdl.handle.net/10033/6230941741-7007BMC biologyenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalBMCoai:repository.helmholtz-hzi.de:10033/6230952021-11-12T03:19:16Zcom_10033_620722col_10033_620723The lytic siphophage vB_StyS-LmqsSP1 reduces Typhimurium isolates on chicken skin.Shakeri, GolshanHammerl, Jens AJamshidi, AbdollahGhazvini, KiarashRohde, ManfredSzabo, IstvanKehrenberg, CorinnaPlötz, MadeleineKittler, SophieHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Phage-based biocontrol of bacteria is considered as a natural approach to combat food-borne pathogens. Salmonella spp. are notifiable and highly prevalent pathogens that cause foodborne diseases globally. In this study, six bacteriophages were isolated and further characterized that infect food-derived Salmonella isolates from different meat sources. The siphovirus VB_StyS-LmqsSP1, which was isolated from a cow´s nasal swab, was further subjected to in-depth characterization. Phage-host interaction investigations in liquid medium showed that vB_StyS-LmqsSP1 can suppress the growth of Salmonella spp. isolates at 37°C for ten hours and reduce the bacterial titer at 4°C significantly. A reduction of 1.4 to 3 log units was observed in investigations with two food-derived Salmonella isolates and one reference strain under cooling conditions using MOIs of 104 and 105. Phage application on chicken skin resulted in a reduction of about 2 log units in the tested Salmonella isolates from the first three hours throughout a one-week experiment at cooling temperature and an MOI of 105. The one-step growth curve analysis using vB_StyS-LmqsSP1 demonstrated a 60-min latent period and a burst size of 50-61 PFU/infected cell for all tested hosts. Furthermore, the genome of the phage was determined to be free from genes causing undesired effects. Based on the phenotypic and genotypic properties, LmqsSP1 was assigned as a promising candidate for biocontrol of Salmonella Typhimurium in food. Importance: Salmonella enterica is one of the major global causes of foodborne enteritis in humans. The use of chemical sanitizers for reducing bacterial pathogens in the food chain can result in the spread of bacterial resistance. Targeted and clean label intervention strategies can reduce Salmonella contamination in food. The significance of our research demonstrates the suitability of a bacteriophage (vB_StyS-LmqsSP1) for biocontrol of Salmonella enterica serovar Typhimurium on poultry due to its lytic efficacy under conditions prevailing in food production environments.2021-11-112021-11-112021-09-29ArticleCells. 2021 Sep 3;10(9):2299. doi: 10.3390/cells10092299.3458690610.1128/AEM.01424-21http://hdl.handle.net/10033/6230951098-5336Cellsenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalMDPIoai:repository.helmholtz-hzi.de:10033/6231992022-06-14T01:54:52Zcom_10033_620722col_10033_620723Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner.Patnaik, AbhisarikaSpiombi, EleonoraFrasca, AngelisaLandsberger, NicolettaZagrebelsky, MartaKorte, MartinBDNFCdkl5FTY720FingolimodMecp2Rett syndromedendritesdendritic spinesprimary culturesThe brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.2022-06-132022-06-132020-04-272020-03-30Article3234928310.3390/ijms21093079http://hdl.handle.net/10033/6231991422-0067International journal of molecular sciencesenhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 InternationalMDPI