2024-03-28T14:04:52Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/3260722019-08-30T11:35:39Zcom_10033_620722col_10033_620723
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
Heneka, Michael T
Kummer, Markus P
Stutz, Andrea
Delekate, Andrea
Schwartz, Stephanie
Vieira-Saecker, Ana
Griep, Angelika
Axt, Daisy
Remus, Anita
Tzeng, Te-Chen
Gelpi, Ellen
Halle, Annett
Korte, Martin
Latz, Eicke
Golenbock, Douglas T
Alzheimer'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.
2014-09-12T12:03:02Z
2014-09-12T12:03:02Z
2013-01-31
Article
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Nature
1476-4687
23254930
10.1038/nature11729
http://hdl.handle.net/10033/326072
Nature
en
Archived with thanks to Nature
oai:repository.helmholtz-hzi.de:10033/5839082019-08-30T11:33:02Zcom_10033_620722col_10033_620723
Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus
Monory, K.
Polack, M.
Remus, A.
Lutz, B.
Korte, M.
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2015-12-15T12:57:32Z
2015-12-15T12:57:32Z
2015-03-04
Article
Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus 2015, 35 (9):3842 Journal of Neuroscience
0270-6474
1529-2401
10.1523/JNEUROSCI.3167-14.2015
http://hdl.handle.net/10033/583908
Journal of Neuroscience
http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.3167-14.2015
oai:repository.helmholtz-hzi.de:10033/6154952019-08-30T11:30:58Zcom_10033_620722col_10033_620723
The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.
Klevanski, Maja
Herrmann, Ulrike
Weyer, Sascha W
Fol, Romain
Cartier, Nathalie
Wolfer, David P
Caldwell, John H
Korte, Martin
Müller, Ulrike C
Helmholtz 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.
2016-07-05T08:44:37Z
2016-07-05T08:44:37Z
2015-12-09
Article
The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. 2015, 35 (49):16018-33 J. Neurosci.
1529-2401
26658856
10.1523/JNEUROSCI.2009-15.2015
http://hdl.handle.net/10033/615495
The Journal of neuroscience : the official journal of the Society for Neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6156512019-08-30T11:30:58Zcom_10033_620722col_10033_620723
Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth.
Chen, Jian-Hua
Kellner, Yves
Zagrebelsky, Marta
Grunwald, Matthias
Korte, Martin
Walla, Peter Jomo
Helmholtz 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.
2016-07-07T08:37:07Z
2016-07-07T08:37:07Z
2015
Article
Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth. 2015, 10 (5):e0128241 PLoS ONE
1932-6203
26020927
10.1371/journal.pone.0128241
http://hdl.handle.net/10033/615651
PloS one
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210752019-08-30T11:37:24Zcom_10033_620722col_10033_620723
Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity.
Ludewig, Susann
Korte, Martin
Hemholtz 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.
2017-08-23T14:27:58Z
2017-08-23T14:27:58Z
2016
Article
Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity. 2016, 9:161 Front Mol Neurosci
1662-5099
28163673
10.3389/fnmol.2016.00161
http://hdl.handle.net/10033/621075
Frontiers in molecular neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211982019-08-30T11:30:58Zcom_10033_620722col_10033_620723
Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease.
Li, Qin
Navakkode, Sheeja
Rothkegel, Martin
Soong, Tuck Wah
Sajikumar, Sreedharan
Korte, Martin
Helmholtz-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.
2017-12-08T15:17:03Z
2017-12-08T15:17:03Z
2017-05-23
Article
Metaplasticity 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.
1091-6490
28484012
10.1073/pnas.1613700114
http://hdl.handle.net/10033/621198
Proceedings of the National Academy of Sciences of the United States of America
PMC5448214
en
https://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_620723
APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission.
Schilling, Sandra
Mehr, Annika
Ludewig, Susann
Stephan, Jonathan
Zimmermann, Marius
August, Alexander
Strecker, Paul
Korte, Martin
Koo, Edward H
Müller, Ulrike C
Kins, Stefan
Eggert, Simone
Helmholtz-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.
2017-12-18T14:48:03Z
2017-12-18T14:48:03Z
2017-05-24
Article
APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission. 2017, 37 (21):5345-5365 J. Neurosci.
1529-2401
28450540
10.1523/JNEUROSCI.1875-16.2017
http://hdl.handle.net/10033/621209
The Journal of neuroscience : the official journal of the Society for Neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213572019-08-30T11:34:22Zcom_10033_620722col_10033_620723
Imbalance of synaptic actin dynamics as a key to fragile X syndrome?
Michaelsen-Preusse, Kristin
Feuge, Jonas
Korte, Martin
Helmholtz-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.
2018-04-18T08:57:55Z
2018-04-18T08:57:55Z
2018-01-30
Article
Imbalance of synaptic actin dynamics as a key to fragile X syndrome? 2018 J. Physiol. (Lond.)
1469-7793
29380377
10.1113/JP275571
http://hdl.handle.net/10033/621357
The Journal of physiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6214052019-08-30T11:28:46Zcom_10033_620722col_10033_620723
A guiding map for inflammation.
Netea, Mihai G
Balkwill, Frances
Chonchol, Michel
Cominelli, Fabio
Donath, Marc Y
Giamarellos-Bourboulis, Evangelos J
Golenbock, Douglas
Gresnigt, Mark S
Heneka, Michael T
Hoffman, Hal M
Hotchkiss, Richard
Joosten, Leo A B
Kastner, Daniel L
Korte, Martin
Latz, Eicke
Libby, Peter
Mandrup-Poulsen, Thomas
Mantovani, Alberto
Mills, Kingston H G
Nowak, Kristen L
O'Neill, Luke A
Pickkers, Peter
van der Poll, Tom
Ridker, Paul M
Schalkwijk, Joost
Schwartz, David A
Siegmund, Britta
Steer, Clifford J
Tilg, Herbert
van der Meer, Jos W M
van de Veerdonk, Frank L
Dinarello, Charles A
Helmholtz-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.
2018-06-21T08:33:47Z
2018-06-21T08:33:47Z
2017-07-19
Article
1529-2916
28722720
10.1038/ni.3790
http://hdl.handle.net/10033/621405
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Nature immunology
oai:repository.helmholtz-hzi.de:10033/6216222019-08-30T11:33:01Zcom_10033_620722col_10033_620723
Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus.
Zimmermann, Tina
Maroso, Mattia
Beer, Annika
Baddenhausen, Sarah
Ludewig, Susann
Fan, Wenqiang
Vennin, Constance
Loch, Sebastian
Berninger, Benedikt
Hofmann, Clementine
Korte, Martin
Soltesz, Ivan
Lutz, Beat
Leschik, Julia
HZI,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.
2018-12-19T13:46:39Z
2018-12-19T13:46:39Z
2018-10-11
Article
1460-2199
30307491
10.1093/cercor/bhy258
http://hdl.handle.net/10033/621622
PMC6215469
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Oxford University Publishing
Cerebral cortex (New York, N.Y. : 1991)
oai:repository.helmholtz-hzi.de:10033/6216282019-08-30T11:30:28Zcom_10033_620722col_10033_620723
The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology.
Martinez Hernandez, Ana
Urbanke, Hendrik
Gillman, Alan L
Lee, Joon
Ryazanov, Sergey
Agbemenyah, Hope Y
Benito, Eva
Jain, Gaurav
Kaurani, Lalit
Grigorian, Gayane
Leonov, Andrei
Rezaei-Ghaleh, Nasrollah
Wilken, Petra
Arce, Fernando Teran
Wagner, Jens
Fuhrmann, Martin
Caruana, Mario
Camilleri, Angelique
Vassallo, Neville
Zweckstetter, Markus
Benz, Roland
Giese, Armin
Schneider, Anja
Korte, Martin
Lal, Ratnesh
Griesinger, Christian
Eichele, Gregor
Fischer, Andre
Alzheimer's disease
Aβ channels
amyloid pathology
gene expression
membrane pores
Alzheimer'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.
2019-01-03T13:39:01Z
2019-01-03T13:39:01Z
2018-01-01
Article
1757-4684
29208638
10.15252/emmm.201707825
http://hdl.handle.net/10033/621628
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
EMBO molecular medicine
oai:repository.helmholtz-hzi.de:10033/6217262019-08-30T11:32:16Zcom_10033_620722col_10033_620723
Immune Challenge Alters Reactivity of Hippocampal Noradrenergic System in Prenatally Stressed Aged Mice.
Grigoryan, Gayane
Lonnemann, Niklas
Korte, Martin
HZI, 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 (via
2019-03-19T08:55:28Z
2019-03-19T08:55:28Z
2019-01-01
Article
Neural Plast. 2019 Jan 21;2019:3152129. doi: 10.1155/2019/3152129. eCollection 2019.
1687-5443
30804990
10.1155/2019/3152129
http://hdl.handle.net/10033/621726
Neural plasticity
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Hindawi
Neural plasticity
oai:repository.helmholtz-hzi.de:10033/6217942019-08-30T11:33:00Zcom_10033_620722col_10033_620723
Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.
Namikawa, Kazuhiko
Dorigo, Alessandro
Zagrebelsky, Marta
Russo, Giulio
Kirmann, Toni
Fahr, Wieland
Dübel, Stefan
Korte, Martin
Köster, Reinhard W
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Purkinje cells
bioimaging
cerebellum
neuronal degeneration
spinocerebellar ataxia
zebrafish
Purkinje 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.
2019-06-03T14:22:03Z
2019-06-03T14:22:03Z
2019-05-15
Article
J Neurosci. 2019 May 15;39(20):3948-3969. doi: 10.1523/JNEUROSCI.1862-18.2019. Epub 2019 Mar 12.
1529-2401
30862666
10.1523/JNEUROSCI.1862-18.2019
http://hdl.handle.net/10033/621794
The journal of neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Society of Neuroscience
The Journal of neuroscience : the official journal of the Society for Neuroscience
oai:repository.helmholtz-hzi.de:10033/6220072019-11-07T01:59:59Zcom_10033_620722col_10033_620723
Fast Regulation of GABAR Diffusion Dynamics by Nogo-A Signaling.
Fricke, Steffen
Metzdorf, Kristin
Ohm, Melanie
Haak, Stefan
Heine, Martin
Korte, Martin
Zagrebelsky, Marta
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
EI balance
GABAARs
Nogo-A
S1PR2
calcineurin
excitation
inhibition
quantum dots
single particle tracking
synaptic plasticity
Precisely 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.
2019-11-06T15:36:07Z
2019-11-06T15:36:07Z
2019-10-15
Article
Cell Rep. 2019 Oct 15;29(3):671-684.e6. doi: 10.1016/j.celrep.2019.09.015.
2211-1247
31618635
10.1016/j.celrep.2019.09.015
http://hdl.handle.net/10033/622007
Cell Reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
Cell reports
oai:repository.helmholtz-hzi.de:10033/6220612020-01-04T02:01:22Zcom_10033_620722col_10033_620723
Amyloid, APP, and Electrical Activity of the Brain.
Hefter, Dimitri
Ludewig, Susann
Draguhn, Andreas
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
APP
Alzheimer’s disease
amyloid
oscillations
plasticity
synaptic transmission
The 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.
2020-01-03T14:27:43Z
2020-01-03T14:27:43Z
2019-11-29
Article
Neuroscientist. 2019 Nov 29:1073858419882619. doi: 10.1177/1073858419882619.
1089-4098
31779518
10.1177/1073858419882619
http://hdl.handle.net/10033/622061
The neuroscientist
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Sage Publikations
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
oai:repository.helmholtz-hzi.de:10033/6222852020-06-10T01:29:38Zcom_10033_620722com_10033_620601col_10033_620723col_10033_620602
Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS.
Hosseini, Shirin
Michaelsen-Preusse, Kristin
Grigoryan, Gayane
Chhatbar, Chintan
Kalinke, Ulrich
Korte, Martin
HZI,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.
2020-06-09T09:03:41Z
2020-06-09T09:03:41Z
Article
Cell Rep. 2020;31(7):107666. doi:10.1016/j.celrep.2020.107666.
32433975
10.1016/j.celrep.2020.107666
http://hdl.handle.net/10033/622285
2211-1247
Cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier (Cell Press)
31
7
107666
Cell reports
United States
oai:repository.helmholtz-hzi.de:10033/6223122020-06-26T02:39:38Zcom_10033_620722com_10033_620626com_10033_620636col_10033_620723col_10033_620627col_10033_620638
Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function.
Hosseini, Shirin
Wilk, Esther
Michaelsen-Preusse, Kristin
Gerhauser, Ingo
Baumgärtner, Wolfgang
Geffers, Robert
Schughart, Klaus
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
dendritic spines
hippocampus
influenza
microglia
neuroinflammation
structural plasticity
Acute 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.
2020-06-25T09:55:48Z
2020-06-25T09:55:48Z
2018-02-27
Article
Other
. J Neurosci. 2018;38(12):3060-3080. doi:10.1523/JNEUROSCI.1740-17.2018.
29487124
10.1523/JNEUROSCI.1740-17.2018
http://hdl.handle.net/10033/622312
1529-2401
The Journal of neuroscience : the official journal of the Society for Neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Society for Neuroscience
38
12
3060
3080
The Journal of neuroscience : the official journal of the Society for Neuroscience
United States
oai:repository.helmholtz-hzi.de:10033/6223522020-07-16T02:29:01Zcom_10033_620722col_10033_620723
BDNF signaling during the lifetime of dendritic spines.
Zagrebelsky, Marta
Tacke, Charlotte
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Brain-derived neurotrophic factor
Dendritic spines
Neurotrophin
TrkB
p75NTR
Dendritic 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.
2020-07-15T12:47:50Z
2020-07-15T12:47:50Z
2020-06-14
Article
Other
Cell Tissue Res. 2020;10.1007/s00441-020-03226-5. doi:10.1007/s00441-020-03226-5.
32537724
10.1007/s00441-020-03226-5
http://hdl.handle.net/10033/622352
1432-0878
Cell and tissue research
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Sringer Nature
Cell and tissue research
Germany
oai:repository.helmholtz-hzi.de:10033/6223752020-08-04T02:35:17Zcom_10033_620722col_10033_620723
Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent.
Beyer, Marianna M S
Lonnemann, Niklas
Remus, Anita
Latz, Eicke
Heneka, Michael T
Korte, Martin
APP/PS1
LPS
NLRP3
hippocampus
neuroinflammation
sepsis
Neuroinflammation 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.
2020-08-03T10:47:40Z
2020-08-03T10:47:40Z
2020-06-04
Article
J Neurosci. 2020;40(28):5480-5494. doi:10.1523/JNEUROSCI.0200-20.2020.
32499379
10.1523/JNEUROSCI.0200-20.2020
http://hdl.handle.net/10033/622375
1529-2401
The Journal of neuroscience : the official journal of the Society for Neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Society for Neuroscience
40
28
5480
5494
The Journal of neuroscience : the official journal of the Society for Neuroscience
United States
oai:repository.helmholtz-hzi.de:10033/6225202021-07-06T11:57:20Zcom_10033_620722com_10033_622921col_10033_622925col_10033_620723
Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs.
Cornelius, Angela D A
Hosseini, Shirin
Schreier, Sarah
Fritzsch, David
Weichert, Loreen
Michaelsen-Preusse, Kristin
Fendt, Markus
Kröger, Andrea
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Hippocampus
Inapparent infection
Langat virus
Learning and memory
Tick-borne encephalitis virus
Type I interferon
To 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.
2020-10-19T13:16:03Z
2020-10-19T13:16:03Z
2020-09-20
Article
Neuroinflammation. 2020 Sep 20;17(1):278. doi: 10.1186/s12974-020-01951-w.
32951602
10.1186/s12974-020-01951-w
http://hdl.handle.net/10033/622520
1742-2094
Journal of neuroinflammation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BioMed Central
17
1
278
Journal of neuroinflammation
England
oai:repository.helmholtz-hzi.de:10033/6225952020-11-19T05:37:23Zcom_10033_620722col_10033_620723
The impact of the digital revolution
on human brain and behavior: where
do we stand?
.
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
addiction
adolescence
amygdala
attention
brain development
cognitive neuroscience
digital media
language development
prefrontal cortex
This 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.
2020-11-18T15:37:11Z
2020-11-18T15:37:11Z
Article
Dialogues Clin Neurosci. 2020 Jun;22(2):101-111. doi: 10.31887/DCNS.2020.22.2/mkorte.
32699510
10.31887/DCNS.2020.22.2/mkorte
http://hdl.handle.net/10033/622595
1958-5969
Dialogues in clinical neuroscience
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Laboratoires Servier
22
2
101
111
Dialogues in clinical neuroscience
France
oai:repository.helmholtz-hzi.de:10033/6226692021-01-09T01:46:02Zcom_10033_620722col_10033_620723
The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer's disease.
Lonnemann, Niklas
Hosseini, Shirin
Marchetti, Carlo
Skouras, Damaris B
Stefanoni, Davide
D'Alessandro, Angelo
Dinarello, Charles A
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Alzheimer’s disease synaptic
cognitive function
synaptic plasticity
Numerous 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.
2021-01-08T15:17:47Z
2021-01-08T15:17:47Z
2020-11-30
Article
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32145-32154. doi: 10.1073/pnas.2009680117. Epub 2020 Nov 30.
33257576
10.1073/pnas.2009680117
http://hdl.handle.net/10033/622669
1091-6490
Proceedings of the National Academy of Sciences of the United States of America
en
http://creativecommons.org/licenses/by-nc-nd/4.0/
Attribution-NonCommercial-NoDerivatives 4.0 International
National Academy of Sciences
117
50
32145
32154
Proceedings of the National Academy of Sciences of the United States of America
United States
United States
United States
oai:repository.helmholtz-hzi.de:10033/6228172021-04-02T01:38:20Zcom_10033_620722col_10033_620723
Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology.
Patnaik, Abhisarika
Zagrebelsky, Marta
Korte, Martin
Holz, Andreas
HZI,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.
2021-04-01T14:20:01Z
2021-04-01T14:20:01Z
2020-08-07
Article
Sci Rep. 2020 Aug 7;10(1):13322. doi: 10.1038/s41598-020-70153-4.
32770070
10.1038/s41598-020-70153-4
http://hdl.handle.net/10033/622817
2045-2322
Scientific reports
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
NPG
10
1
13322
Scientific reports
England
oai:repository.helmholtz-hzi.de:10033/6229002021-06-12T01:45:53Zcom_10033_620722col_10033_620723
Respiratory viral infections and associated neurological manifestations
Hosseini, Shirin
Michaelsen-Preusse, Kristin
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Neurology
Clinical Neurology
central nervous system
coronavirus
influenza virus
neurodegeneration
respiratory viral infections
Respiratory 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.
2021-06-11T09:14:38Z
2021-06-11T09:14:38Z
2021-03-29
Review
Neuroforum, 27, (2), 2021, pp. 53-65. https://doi.org/10.1515/nf-2020-0035
0947-0875
10.1515/nf-2020-0035
http://hdl.handle.net/10033/622900
2363-7013
Neuroforum
10.1515/nf-2020-0035
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Walter de Gruyter GmbH
0
0
Neuroforum
oai:repository.helmholtz-hzi.de:10033/6230472021-09-28T01:47:56Zcom_10033_620722com_10033_620626col_10033_620723col_10033_620627
Long-Term Consequence of Non-neurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer's Disease Symptoms.
Hosseini, Shirin
Michaelsen-Preusse, Kristin
Schughart, Klaus
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Alzheimer’s disease
behavior
hippocampus
influenza virus
microglia
synaptic plasticity
Influenza 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.
2021-09-27T12:52:04Z
2021-09-27T12:52:04Z
2021-04-28
Article
Front Cell Neurosci. 2021 Apr 28;15:643650. doi: 10.3389/fncel.2021.643650.
1662-5102
33994946
10.3389/fncel.2021.643650
http://hdl.handle.net/10033/623047
Frontiers in cellular neuroscience
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Frontiers
15
643650
Frontiers in cellular neuroscience
Switzerland
oai:repository.helmholtz-hzi.de:10033/6230512021-09-29T01:53:03Zcom_10033_620722col_10033_620723
Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism-like phenotype.
Steubler, Vicky
Erdinger, Susanne
Back, Michaela K
Ludewig, Susann
Fässler, Dominique
Richter, Max
Han, Kang
Slomianka, Lutz
Amrein, Irmgard
von Engelhardt, Jakob
Wolfer, David P
Korte, Martin
Müller, Ulrike C
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Alzheimer
Amyloid precursor protein
Autism spectrum disorder
learning and memory
synaptic plasticity
The 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.
2021-09-28T15:06:14Z
2021-09-28T15:06:14Z
2021-05-19
Article
EMBO J. 2021 Jun 15;40(12):e107471. doi: 10.15252/embj.2020107471. Epub 2021 May 19.
34008862
10.15252/embj.2020107471
http://hdl.handle.net/10033/623051
1460-2075
The EMBO journal
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Wiley/EMBO Press
40
12
e107471
The EMBO journal
England
oai:repository.helmholtz-hzi.de:10033/6230942021-11-26T16:55:42Zcom_10033_620722col_10033_620723
Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling.
Petkova-Tuffy, Andonia
Gödecke, Nina
Viotti, Julio
Korte, Martin
Dresbach, Thomas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Neuroligin-1,Brain-derived neurotrophic factor
Presynaptic maturation
Background: 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.
2021-11-11T14:07:27Z
2021-11-11T14:07:27Z
2021-09-27
Article
J Biol Chem. 2021 Oct 9;297(5):101298. doi: 10.1016/j.jbc.2021.101298. Epub ahead of print. PMID: 34637789.
34579720
10.1186/s12915-021-01145-7
http://hdl.handle.net/10033/623094
1741-7007
BMC biology
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
BMC
19
1
215
BMC biology
England
oai:repository.helmholtz-hzi.de:10033/6230952021-11-12T03:19:16Zcom_10033_620722col_10033_620723
The lytic siphophage vB_StyS-LmqsSP1 reduces Typhimurium isolates on chicken skin.
Shakeri, Golshan
Hammerl, Jens A
Jamshidi, Abdollah
Ghazvini, Kiarash
Rohde, Manfred
Szabo, Istvan
Kehrenberg, Corinna
Plötz, Madeleine
Kittler, Sophie
HZI,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.
2021-11-11T14:27:51Z
2021-11-11T14:27:51Z
2021-09-29
Article
Cells. 2021 Sep 3;10(9):2299. doi: 10.3390/cells10092299.
34586906
10.1128/AEM.01424-21
http://hdl.handle.net/10033/623095
1098-5336
Cells
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
AEM0142421
Applied and environmental microbiology
United States
oai:repository.helmholtz-hzi.de:10033/6231992022-06-14T01:54:52Zcom_10033_620722col_10033_620723
Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner.
Patnaik, Abhisarika
Spiombi, Eleonora
Frasca, Angelisa
Landsberger, Nicoletta
Zagrebelsky, Marta
Korte, Martin
BDNF
Cdkl5
FTY720
Fingolimod
Mecp2
Rett syndrome
dendrites
dendritic spines
primary cultures
The 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.
2022-06-13T08:08:55Z
2022-06-13T08:08:55Z
2020-04-27
2020-03-30
Article
32349283
10.3390/ijms21093079
http://hdl.handle.net/10033/623199
1422-0067
International journal of molecular sciences
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
21
9
International journal of molecular sciences
Switzerland