Publications by authors named "Martin Fuhrmann"

30 Publications

  • Page 1 of 1

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.

Mol Psychiatry 2021 Apr 9. Epub 2021 Apr 9.

INSERM UMR-S 1270, Paris, France.

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.
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http://dx.doi.org/10.1038/s41380-021-01081-6DOI Listing
April 2021

Hippocampal hyperactivity in a rat model of Alzheimer's disease.

J Neurochem 2021 Feb 14. Epub 2021 Feb 14.

Neuronal Networks Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aβ) deposition. We established two-photon Ca -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aβ-deposition and disease progression.
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http://dx.doi.org/10.1111/jnc.15323DOI Listing
February 2021

Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability.

Cell Death Differ 2020 12 8;27(12):3354-3373. Epub 2020 Jul 8.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.
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http://dx.doi.org/10.1038/s41418-020-0584-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853040PMC
December 2020

Memory trace interference impairs recall in a mouse model of Alzheimer's disease.

Nat Neurosci 2020 08 8;23(8):952-958. Epub 2020 Jun 8.

Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD.
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http://dx.doi.org/10.1038/s41593-020-0652-4DOI Listing
August 2020

Tagger-A Swiss army knife for multiomics to dissect cell type-specific mechanisms of gene expression in mice.

PLoS Biol 2019 08 8;17(8):e3000374. Epub 2019 Aug 8.

Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

A deep understanding of how regulation of the multiple levels of gene expression in mammalian tissues give rise to complex phenotypes has been impeded by cellular diversity. A handful of techniques were developed to tag-select nucleic acids of interest in specific cell types, thereby enabling their capture. We expanded this strategy by developing the Tagger knock-in mouse line bearing a quad-cistronic transgene combining enrichment tools for nuclei, nascent RNA, translating mRNA, and mature microRNA (miRNA). We demonstrate that Tagger can capture the desired nucleic acids, enabling multiple omics approaches to be applied to specific cell types in vivo using a single transgenic mouse line.
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http://dx.doi.org/10.1371/journal.pbio.3000374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701817PMC
August 2019

Unsupervised excitation: GABAergic dysfunctions in Alzheimer's disease.

Brain Res 2019 03 29;1707:216-226. Epub 2018 Nov 29.

German Center for Neurodegenerative Diseases, Neuroimmunology and Imaging Group, Sigmund-Freud-Str. 27, 53127 Bonn, Germany. Electronic address:

Alzheimer's disease (AD) is characterized by the classical hallmarks of Aβ-deposition and tau-pathology that are thought to ultimately lead to synapse and neuron loss. Although long known, neuroinflammation has recently attracted a substantial amount of attention by researchers due to genome wide association studies (GWAS) that identified microglia associated genes to be correlated with sporadic AD. Besides that, cholinergic degeneration and gamma-aminobutyric acid (GABA) abnormalities have been identified in the brains of AD patients already decades ago, but have not received much attention over the last ten years. Recently, the neuronal network dysfunction hypothesis has revived interest in how impairments of neuronal communication at the network level lead to epileptiform activity and disrupted oscillations observed in the brains of AD patients and mouse models. Thereby, deficits in neuronal networks involved in learning and memory might ultimately cause memory impairments. In this context, an imbalance between excitation and inhibition has been hypothesized to contribute to neuronal network dysfunction. Here, disturbances of cholinergic and GABAergic transmission might play a crucial role. In this review, we will focus on GABAergic dysfunction in AD and mouse models of AD and how those might relate to neuronal network aberration and memory impairment.
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http://dx.doi.org/10.1016/j.brainres.2018.11.042DOI Listing
March 2019

Chronic 2P-STED imaging reveals high turnover of dendritic spines in the hippocampus in vivo.

Elife 2018 06 22;7. Epub 2018 Jun 22.

Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Bordeaux, France.

Rewiring neural circuits by the formation and elimination of synapses is thought to be a key cellular mechanism of learning and memory in the mammalian brain. Dendritic spines are the postsynaptic structural component of excitatory synapses, and their experience-dependent plasticity has been extensively studied in mouse superficial cortex using two-photon microscopy in vivo. By contrast, very little is known about spine plasticity in the hippocampus, which is the archetypical memory center of the brain, mostly because it is difficult to visualize dendritic spines in this deeply embedded structure with sufficient spatial resolution. We developed chronic 2P-STED microscopy in mouse hippocampus, using a 'hippocampal window' based on resection of cortical tissue and a long working distance objective for optical access. We observed a two-fold higher spine density than previous studies and measured a spine turnover of ~40% within 4 days, which depended on spine size. We thus provide direct evidence for a high level of structural rewiring of synaptic circuits and new insights into the structure-dynamics relationship of hippocampal spines. Having established chronic super-resolution microscopy in the hippocampus in vivo, our study enables longitudinal and correlative analyses of nanoscale neuroanatomical structures with genetic, molecular and behavioral experiments.
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http://dx.doi.org/10.7554/eLife.34700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014725PMC
June 2018

P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model.

J Exp Med 2018 06 3;215(6):1649-1663. Epub 2018 May 3.

German Center for Neurodegenerative Diseases, Bonn, Germany

Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer's disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation. These effects occur independently from β-amyloid metabolism or plaque burden but are associated with a higher morphological complexity of periplaque reactive astrocytes, as well as reduced dystrophic neurite burden and greater plaque compaction. Importantly, APPPS1 mice chronically treated with P2Y1R antagonists, as well as APPPS1 mice carrying an astrocyte-specific genetic deletion (Ip3r2) of signaling pathways downstream of P2Y1R activation, are protected from the decline of spatial learning and memory. In summary, our study establishes the restoration of network homoeostasis by P2Y1R inhibition as a novel treatment target in AD.
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http://dx.doi.org/10.1084/jem.20171487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987918PMC
June 2018

The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology.

EMBO Mol Med 2018 01;10(1):32-47

Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany

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.
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http://dx.doi.org/10.15252/emmm.201707825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760857PMC
January 2018

Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain.

Immunity 2017 06;46(6):1030-1044.e8

Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel. Electronic address:

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.
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http://dx.doi.org/10.1016/j.immuni.2017.05.003DOI Listing
June 2017

Recent advances in applying mass spectrometry and systems biology to determine brain dynamics.

Expert Rev Proteomics 2017 06 1;14(6):545-559. Epub 2017 Jun 1.

b Medicum, Meilahti Clinical Proteomics Core Facility, Biochemistry/Developmental Biology, Faculty of Medicine , FI-00014 University of Helsinki , Helsinki , Finland.

Introduction: Neurological disorders encompass various pathologies which disrupt normal brain physiology and function. Poor understanding of their underlying molecular mechanisms and their societal burden argues for the necessity of novel prevention strategies, early diagnostic techniques and alternative treatment options to reduce the scale of their expected increase. Areas covered: This review scrutinizes mass spectrometry based approaches used to investigate brain dynamics in various conditions, including neurodegenerative and neuropsychiatric disorders. Different proteomics workflows for isolation/enrichment of specific cell populations or brain regions, sample processing; mass spectrometry technologies, for differential proteome quantitation, analysis of post-translational modifications and imaging approaches in the brain are critically deliberated. Future directions, including analysis of cellular sub-compartments, targeted MS platforms (selected/parallel reaction monitoring) and use of mass cytometry are also discussed. Expert commentary: Here, we summarize and evaluate current mass spectrometry based approaches for determining brain dynamics in health and diseases states, with a focus on neurological disorders. Furthermore, we provide insight on current trends and new MS technologies with potential to improve this analysis.
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http://dx.doi.org/10.1080/14789450.2017.1335200DOI Listing
June 2017

Dysfunction of Somatostatin-Positive Interneurons Associated with Memory Deficits in an Alzheimer's Disease Model.

Neuron 2016 Oct 15;92(1):114-125. Epub 2016 Sep 15.

Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. Electronic address:

Alzheimer's disease (AD) is characterized by cognitive decline and neuronal network dysfunction, but the underlying mechanisms remain unknown. In the hippocampus, microcircuit activity during learning and memory processes is tightly controlled by O-LM interneurons. Here, we investigated the effect of beta-amyloidosis on O-LM interneuron structural and functional connectivity, combining two-photon in vivo imaging of synaptic morphology, awake Ca imaging, and retrograde mono-transsynaptic rabies tracing. We find severely impaired synaptic rewiring that occurs on the O-LM interneuron input and output level in a mouse model of AD. Synaptic rewiring that occurs upon fear learning on O-LM interneuron input level is affected in mice with AD-like pathology. This process requires the release of acetylcholine from septo-hippocampal projections. We identify decreased cholinergic action on O-LM interneurons in APP/PS1 mice as a key pathomechanism that contributes to memory impairment in a mouse model, with potential relevance for human AD.
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http://dx.doi.org/10.1016/j.neuron.2016.08.034DOI Listing
October 2016

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Acta Neuropathol 2015 Nov 6;130(5):619-31. Epub 2015 Oct 6.

German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.
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http://dx.doi.org/10.1007/s00401-015-1483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612332PMC
November 2015

Locomotion, Theta Oscillations, and the Speed-Correlated Firing of Hippocampal Neurons Are Controlled by a Medial Septal Glutamatergic Circuit.

Neuron 2015 Jun 14;86(5):1253-64. Epub 2015 May 14.

Neuronal Networks Group, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53127 Bonn, Germany. Electronic address:

Before the onset of locomotion, the hippocampus undergoes a transition into an activity-state specialized for the processing of spatially related input. This brain-state transition is associated with increased firing rates of CA1 pyramidal neurons and the occurrence of theta oscillations, which both correlate with locomotion velocity. However, the neural circuit by which locomotor activity is linked to hippocampal oscillations and neuronal firing rates is unresolved. Here we reveal a septo-hippocampal circuit mediated by glutamatergic (VGluT2(+)) neurons that is activated before locomotion onset and that controls the initiation and velocity of locomotion as well as the entrainment of theta oscillations. Moreover, via septo-hippocampal projections onto alveus/oriens interneurons, this circuit regulates feedforward inhibition of Schaffer collateral and perforant path input to CA1 pyramidal neurons in a locomotion-dependent manner. With higher locomotion speed, the increased activity of medial septal VGluT2 neurons is translated into increased axo-somatic depolarization and higher firing rates of CA1 pyramidal neurons. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2015.05.001DOI Listing
June 2015

Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.

Acta Neuropathol Commun 2014 Dec 24;2:175. Epub 2014 Dec 24.

Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.
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http://dx.doi.org/10.1186/s40478-014-0175-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293804PMC
December 2014

Long-term in vivo imaging of dendritic spines in the hippocampus reveals structural plasticity.

J Neurosci 2014 Oct;34(42):13948-53

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

Hippocampal function is important for learning and memory. During memory processing, hippocampal CA1 neurons play a crucial role by integrating excitatory synaptic input from CA3 and the entorhinal cortex. These neurons receive excitatory input almost exclusively on dendritic spines. The formation and elimination--structural plasticity--of dendritic spines reflect wiring changes within the hippocampal network. Despite the relevance of the hippocampus in learning and memory, most in vivo data on structural plasticity derive from cortical regions. We established a chronic hippocampal window approach using two-photon microscopy to visualize dendritic spines throughout all CA1 hippocampal layers and over a time course of weeks. Moreover, even granule cells in dentate gyrus could be reliably detected. We found that the spine density in stratum radiatum (∼1.1 per micrometer) remained stable over weeks. However, a small fraction (3.4%) of spines were formed and eliminated between imaging sessions, which demonstrated that spines of CA1 neurons exhibit structural plasticity in adult mice. In addition, we tested for possible inflammatory or behavioral side effects of hippocampal window implantation. Mice exhibited a transient increase in microgliosis and astrogliosis, which declined within a few weeks. We did not detect any difference in behavioral performance in an open-field and contextual fear-conditioning paradigm. In conclusion, hippocampal long-term two-photon imaging revealed structural plasticity of dendritic spines in CA1 pyramidal neurons. This approach may provide a powerful tool to analyze changes in neuronal network rewiring during hippocampal learning and memory processes in health and disease.
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http://dx.doi.org/10.1523/JNEUROSCI.1464-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705298PMC
October 2014

Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium.

Cell 2014 Jan;156(3):456-68

Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany. Electronic address:

The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.
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http://dx.doi.org/10.1016/j.cell.2014.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258064PMC
January 2014

Amyloid plaque formation precedes dendritic spine loss.

Acta Neuropathol 2012 Dec 21;124(6):797-807. Epub 2012 Sep 21.

Center for Neuropathology, Ludwig-Maximilians University, Munich, Germany.

Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics of these processes. In particular, the question as to whether synapse loss precedes or follows plaque formation remains unanswered. To address this question, and to learn more about the underlying kinetics, we simultaneously imaged amyloid plaque deposition and dendritic spine loss by applying two-photon in vivo microscopy through a cranial window in double transgenic APPPS1 mice. As a result, we first observed that the rate of dendritic spine loss in proximity to plaques is the same in both young and aged animals. However, plaque size only increased significantly in the young cohort, indicating that spine loss persists even many months after initial plaque appearance. Tracking the fate of individual spines revealed that net spine loss is caused by increased spine elimination, with the rate of spine formation remaining constant. Imaging of dendritic spines before and during plaque formation demonstrated that spine loss around plaques commences at least 4 weeks after initial plaque formation. In conclusion, spine loss occurs, shortly but with a significant time delay, after the birth of new plaques, and persists in the vicinity of amyloid plaques over many months. These findings hence give further hope to the possibility that there is a therapeutic window between initial amyloid plaque deposition and the onset of structural damage at spines.
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http://dx.doi.org/10.1007/s00401-012-1047-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508278PMC
December 2012

Role of presenilin 1 in structural plasticity of cortical dendritic spines in vivo.

J Neurochem 2011 Dec 24;119(5):1064-73. Epub 2011 Oct 24.

Center for Neuropathology and Prion Research, Laboratory of Experimental Neuropathology, Ludwig-Maximilian-University, Munich, Germany.

Mutations in presenilins are the major cause of familial Alzheimer's disease (FAD), leading to impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Presenilins are the catalytic subunits of γ-secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two-photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over-expressing either human wild-type PS1 or the FAD-mutated variant A246E (FAD-PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over-expressing human wild-type presenilin1 and FAD-PS1, whereas on basal layer 3 dendrites only over-expression of FAD-PS1 increased the spine density. Time-lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ-secretase-dependent processing of synapse-relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca(2+) homeostasis in PS1 over-expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain-of-function but γ-secretase-independent manner.
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http://dx.doi.org/10.1111/j.1471-4159.2011.07503.xDOI Listing
December 2011

In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks.

Acta Neuropathol 2011 Mar 7;121(3):327-35. Epub 2010 Dec 7.

Center of Neuropathology and Prion Research, Ludwig Maximilians Universität, Feodor-Lynen-Strasse 23, Munich, Germany.

The kinetics of amyloid plaque formation and growth as one of the characteristic hallmarks of Alzheimer's disease (AD) are fundamental issues in AD research. Especially the question how fast amyloid plaques grow to their final size after they are born remains controversial. By long-term two-photon in vivo imaging we monitored individual methoxy-X04-stained amyloid plaques over 6 weeks in 12 and 18 months old Tg2576 mice. We found that in 12 months old mice, newly appearing amyloid plaques were initially small in volume and subsequently grew over time. The growth rate of plaques was inversely proportional to their volume; thus amyloid plaques that were already present at the first imaging time point grew over time but slower compared to new plaques. Additionally, we analyzed 18 months old Tg2576 mice in which we neither found newly appearing plaques nor a significant growth of pre-existing plaques over 6 weeks of imaging. In conclusion, newly appearing amyloid plaques are initially small in size but grow over time until plaque growth can not be detected anymore in aged mice. These results suggest that drugs that target plaque formation should be most effective early in the disease, when plaques are growing.
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http://dx.doi.org/10.1007/s00401-010-0787-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038220PMC
March 2011

Multiple events lead to dendritic spine loss in triple transgenic Alzheimer's disease mice.

PLoS One 2010 Nov 16;5(11):e15477. Epub 2010 Nov 16.

Center of Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany.

The pathology of Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss. By means of long-term two-photon in vivo imaging and confocal imaging, we characterized the spatio-temporal pattern of dendritic spine loss for the first time in 3xTg-AD mice. These mice exhibit an early loss of layer III neurons at 4 months of age, at a time when only soluble Aβ is abundant. Later on, dendritic spines are lost around amyloid plaques once they appear at 13 months of age. At the same age, we observed spine loss also in areas apart from amyloid plaques. This plaque independent spine loss manifests exclusively at dystrophic dendrites that accumulate both soluble Aβ and hyperphosphorylated tau intracellularly. Collectively, our data shows that three spatio-temporally independent events contribute to a net loss of dendritic spines. These events coincided either with the occurrence of intracellular soluble or extracellular fibrillar Aβ alone, or the combination of intracellular soluble Aβ and hyperphosphorylated tau.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982845PMC
November 2010

Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease.

Nat Neurosci 2010 Apr 21;13(4):411-3. Epub 2010 Mar 21.

Center of Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.

Microglia, the immune cells of the brain, can have a beneficial effect in Alzheimer's disease by phagocytosing amyloid-beta. Two-photon in vivo imaging of neuron loss in the intact brain of living Alzheimer's disease mice revealed an involvement of microglia in neuron elimination, indicated by locally increased number and migration velocity of microglia around lost neurons. Knockout of the microglial chemokine receptor Cx3cr1, which is critical in neuron-microglia communication, prevented neuron loss.
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http://dx.doi.org/10.1038/nn.2511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072212PMC
April 2010

Real-time imaging reveals the single steps of brain metastasis formation.

Nat Med 2010 Jan 20;16(1):116-22. Epub 2009 Dec 20.

Department of Neurology, Ludwig-Maximilians University, Munich, Germany.

Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.
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http://dx.doi.org/10.1038/nm.2072DOI Listing
January 2010

Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway.

J Neurosci 2009 Aug;29(33):10405-9

Center of Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.

Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by the invariant accumulation of the beta-amyloid peptide (Abeta), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing Abeta levels and amyloid plaque load via modifying or inhibiting the generation of Abeta. Based on in vivo two-photon imaging, we present evidence that side effects on the level of dendritic spines may counteract the beneficial potential of these approaches. Two potent gamma-secretase inhibitors (GSIs), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) and LY450139 (hydroxylvaleryl monobenzocaprolactam), were found to reduce the density of dendritic spines in wild-type mice. In mice deficient for the amyloid precursor protein (APP), both GSIs had no effect on dendritic spine density, demonstrating that gamma-secretase inhibition decreases dendritic spine density via APP. Independent of the effects of gamma-secretase inhibition, we observed a twofold higher density of dendritic spines in the cerebral cortex of adult APP-deficient mice. This observation further supports the notion that APP is involved in the modulation of dendritic spine density--shown here for the first time in vivo.
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http://dx.doi.org/10.1523/JNEUROSCI.2288-09.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665795PMC
August 2009

Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis.

Glia 2009 Sep;57(12):1306-15

Department of Neurology, Ludwig-Maximilians University, Munich, Germany.

Infiltration of cancer cells into normal tissue is a hallmark of malignant gliomas and compromises treatment options. A lack of appropriate models limits the study of this invasion in vivo, which makes it difficult to fully understand its anatomy and the role of dynamic interactions with structures of the normal brain. We developed a novel methodology by utilizing multiphoton laser scanning microscopy (MPLSM) to image the movement of glioma cells deep within the normal brain of live mice in real time. This allowed us to track the invasion of individual RFP-expressing GL261 cells in relation to perfused vasculature or GFP-labeled endothelial cells repetitively over days, up to a depth of 0.5 mm. Glioma cells moved faster and more efficiently when the abluminal site of a blood vessel was utilized for invasion. Cells that invaded perivascularly were frequently found next to (a) multiple capillary structures where microvessels run parallel to each other, (b) capillary loops or glomeruloid-like bodies, and (c) dilated capillaries. Dynamic MPLSM for more than 48 h revealed that single invasive glioma cells induced intussusceptive microvascular growth and capillary loop formation, specifically at the microvascular site with which they had contact. As the main tumor grew by cooption of existing brain vessels, these peritumoral vascular changes may create a beneficial environment for glioma growth. In conclusion, our study revealed new mechanisms of peritumoral angiogenesis and invasion in gliomas, providing an explanation for their interdependence.
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http://dx.doi.org/10.1002/glia.20850DOI Listing
September 2009

Tumor-selective vessel occlusions by platelets after vascular targeting chemotherapy using paclitaxel encapsulated in cationic liposomes.

Int J Cancer 2008 Jan;122(2):452-60

Institute for Surgical Research, University of Munich (LMU), Germany.

Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) significantly impairs tumor growth by a significant reduction of functional tumor microcirculation and induction of endothelial cell apoptosis. The aim of the study was to analyze whether platelet activation within the tumor microcirculation contributes to the antivascular effects of vascular targeting chemotherapy using EndoTAG-1. In vitro, FACS analysis revealed a significant activation of platelets upon treatment with EndoTAG-1. In vivo, using A-Mel-3 tumors in Syrian Golden hamsters equipped with dorsal skinfold chamber preparations, the contribution of platelets to the antivascular effects of EndoTAG-1 was evaluated by fluorescence and laser-scanning microscopy. Immediately after a single treatment with EndoTAG-1 or cationic liposomes devoid of paclitaxel, an increase of platelet adherence in tumor microvessels was observed. This was accompanied by an acute impairment of the microcirculation within the treated tumors leading to reduced tumor perfusion. After repetitive therapy, an increase of platelet adherence and subsequent tumor microvessel occlusions occurred only after treatment with EndoTAG-1. Comparing to "tumor free" normal tissue controls these microthromboses were tumor selective. Significantly disbalancing the coagulation system within tumors by targeted induction of microthromboses within the tumor microcirculation appears to be an important mechanism of EndoTAG-1 therapy.
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http://dx.doi.org/10.1002/ijc.23088DOI Listing
January 2008

Dendritic pathology in prion disease starts at the synaptic spine.

J Neurosci 2007 Jun;27(23):6224-33

Center of Neuropathology and Prion Research, Ludwig Maximilians University, 81377 Munich, Germany.

Spine loss represents a common hallmark of neurodegenerative diseases. However, little is known about the underlying mechanisms, especially the relationship between spine elimination and neuritic destruction. We imaged cortical dendrites throughout a neurodegenerative disease using scrapie in mice as a model. Two-photon in vivo imaging over 2 months revealed a linear decrease of spine density. Interestingly, only persistent spines (lifetime > or = 8 d) disappeared, whereas the density of transient spines (lifetime < or = 4 d) was unaffected. Before spine loss, dendritic varicosities emerged preferentially at sites where spines protrude from the dendrite. These results implicate that the location where the spine protrudes from the dendrite may be particularly vulnerable and that dendritic varicosities may actually cause spine loss.
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http://dx.doi.org/10.1523/JNEUROSCI.5062-06.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672160PMC
June 2007

Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons.

J Neurochem 2006 Sep;98(6):1876-85

Center of Neuropathology and Prion Research, Ludwig Maximilians University, 81377 Munich, Germany.

Previous neurophysiological studies on prion protein deficient (Prnp(-/-)) mice have revealed a significant reduction of slow afterhyperpolarization currents (sI(AHP)) in hippocampal CA1 pyramidal cells. Here we aim to determine whether loss of PrP(C.) directly affects the potassium channels underlying sI(AHP) or if sI(AHP) is indirectly disturbed by altered intracellular Ca(2+) fluxes. Patch-clamp measurements and confocal Ca(2+) imaging in acute hippocampal slice preparations of Prnp(-/-) mice compared to littermate control mice revealed a reduced Ca(2+) rise in CA1 neurons lacking PrP(C) following a depolarization protocol known to induce sI(AHP). Moreover, we observed a reduced Ca(2+) influx via l-type voltage gated calcium channels (VGCCs). No differences were observed in the protein expression of the pore forming alpha1 subunit of VGCCs Prnp(-/-) mice. Surprisingly, the beta2 subunit, critically involved in the transport of the alpha1 subunit to the plasma membrane, was found to be up-regulated in knock out hippocampal tissue. On mRNA level however, no differences could be detected for the alpha1C, D and beta2-4 subunits. In conclusion our data support the notion that lack of PrP(C.) does not directly affect the potassium channels underlying sI(AHP), but modulates these channels due to its effect on the intracellular free Ca(2+) concentration via a reduced Ca(2+) influx through l-type VGCCs.
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http://dx.doi.org/10.1111/j.1471-4159.2006.04011.xDOI Listing
September 2006

Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members.

EMBO J 2004 Oct 23;23(20):4106-15. Epub 2004 Sep 23.

Zentrum für Neuropathologie und Prionforschung, Universität München, München, Germany.

The Alzheimer's disease beta-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2-/-APLP1-/- and APLP2-/-APP-/- mice die postnatally, while APLP1-/-APP-/- mice and single mutants were viable. We now report that mice lacking all three APP/APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81% of triple mutants showed cranial abnormalities. In 68% of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival.
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http://dx.doi.org/10.1038/sj.emboj.7600390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524337PMC
October 2004