• 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. (2016)
      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.
    • 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. (2015-12-09)
      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.
    • 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. (2015-03-04)
    • 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. (2015)
      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.
    • 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; et al. (2013-01-31)
      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.
    • 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.
    • 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.
      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.