The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology
2017; Springer Nature; Volume: 10; Issue: 1 Linguagem: Inglês
10.15252/emmm.201707825
ISSN1757-4684
AutoresAna Martinez Hernandez, Hendrik Urbanke, Alan L. Gillman, Joon Lee, Sergey Ryazanov, H.Y. Agbemenyah, Eva Benito, Gaurav Jain, Lalit Kaurani, Gayane Grigorian, Andrei Leonov, Nasrollah Rezaei‐Ghaleh, Petra Wilken, Fernando Terán Arce, Jens A. Wagner, Martin Fuhrman, Mario Caruana, Angelique Camilleri, Neville Vassallo, Markus Zweckstetter, Roland Benz, Armin Giese, Anja Schneider, Martin Körte, Ratnesh Lal, Christian Griesinger, Gregor Eichele, André Fischer,
Tópico(s)Cholinesterase and Neurodegenerative Diseases
ResumoResearch Article5 December 2017Open Access Transparent process The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology Ana Martinez Hernandez Ana Martinez Hernandez Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Search for more papers by this author Hendrik Urbanke Hendrik Urbanke Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Alan L Gillman Alan L Gillman orcid.org/0000-0002-1312-047X Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Joon Lee Joon Lee Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Sergey Ryazanov Sergey Ryazanov Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Hope Y Agbemenyah Hope Y Agbemenyah Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Search for more papers by this author Eva Benito Eva Benito Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Gaurav Jain Gaurav Jain Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Lalit Kaurani Lalit Kaurani DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Gayane Grigorian Gayane Grigorian Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany Search for more papers by this author Andrei Leonov Andrei Leonov Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Nasrollah Rezaei-Ghaleh Nasrollah Rezaei-Ghaleh Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Petra Wilken Petra Wilken DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany Search for more papers by this author Fernando Teran Arce Fernando Teran Arce Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Jens Wagner Jens Wagner Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Search for more papers by this author Martin Fuhrman Martin Fuhrman Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Search for more papers by this author Mario Caruana Mario Caruana Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Angelique Camilleri Angelique Camilleri Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Neville Vassallo Neville Vassallo Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Markus Zweckstetter Markus Zweckstetter Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany Search for more papers by this author Roland Benz Roland Benz Life Sciences and Chemistry, Jacobs University of Bremen, Bremen, Germany Search for more papers by this author Armin Giese Armin Giese Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany Search for more papers by this author Anja Schneider Anja Schneider DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany Search for more papers by this author Martin Korte Corresponding Author Martin Korte [email protected] orcid.org/0000-0001-6956-5913 Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany Helmholtz Center for Infections Research, Braunschweig, Germany Search for more papers by this author Ratnesh Lal Corresponding Author Ratnesh Lal [email protected] orcid.org/0000-0001-7256-126X Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Christian Griesinger Corresponding Author Christian Griesinger [email protected] orcid.org/0000-0002-1266-4344 Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Gregor Eichele Corresponding Author Gregor Eichele [email protected] orcid.org/0000-0002-2863-9127 Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Search for more papers by this author Andre Fischer Corresponding Author Andre Fischer [email protected] orcid.org/0000-0001-8546-1161 Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Search for more papers by this author Ana Martinez Hernandez Ana Martinez Hernandez Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Search for more papers by this author Hendrik Urbanke Hendrik Urbanke Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Alan L Gillman Alan L Gillman orcid.org/0000-0002-1312-047X Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Joon Lee Joon Lee Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Sergey Ryazanov Sergey Ryazanov Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Hope Y Agbemenyah Hope Y Agbemenyah Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Search for more papers by this author Eva Benito Eva Benito Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Gaurav Jain Gaurav Jain Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Lalit Kaurani Lalit Kaurani DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Gayane Grigorian Gayane Grigorian Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany Search for more papers by this author Andrei Leonov Andrei Leonov Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Nasrollah Rezaei-Ghaleh Nasrollah Rezaei-Ghaleh Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Search for more papers by this author Petra Wilken Petra Wilken DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany Search for more papers by this author Fernando Teran Arce Fernando Teran Arce Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Jens Wagner Jens Wagner Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Search for more papers by this author Martin Fuhrman Martin Fuhrman Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Search for more papers by this author Mario Caruana Mario Caruana Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Angelique Camilleri Angelique Camilleri Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Neville Vassallo Neville Vassallo Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta Search for more papers by this author Markus Zweckstetter Markus Zweckstetter Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany Search for more papers by this author Roland Benz Roland Benz Life Sciences and Chemistry, Jacobs University of Bremen, Bremen, Germany Search for more papers by this author Armin Giese Armin Giese Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany Search for more papers by this author Anja Schneider Anja Schneider DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany Search for more papers by this author Martin Korte Corresponding Author Martin Korte [email protected] orcid.org/0000-0001-6956-5913 Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany Helmholtz Center for Infections Research, Braunschweig, Germany Search for more papers by this author Ratnesh Lal Corresponding Author Ratnesh Lal [email protected] orcid.org/0000-0001-7256-126X Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA Search for more papers by this author Christian Griesinger Corresponding Author Christian Griesinger [email protected] orcid.org/0000-0002-1266-4344 Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany Search for more papers by this author Gregor Eichele Corresponding Author Gregor Eichele [email protected] orcid.org/0000-0002-2863-9127 Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany Search for more papers by this author Andre Fischer Corresponding Author Andre Fischer [email protected] orcid.org/0000-0001-8546-1161 Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany Search for more papers by this author Author Information Ana Martinez Hernandez1,2,‡, Hendrik Urbanke1,‡, Alan L Gillman3,‡, Joon Lee3,‡, Sergey Ryazanov4,5, Hope Y Agbemenyah6, Eva Benito1, Gaurav Jain1, Lalit Kaurani5, Gayane Grigorian7, Andrei Leonov4,5, Nasrollah Rezaei-Ghaleh4,8, Petra Wilken5,6,9, Fernando Teran Arce3,16, Jens Wagner10, Martin Fuhrman10, Mario Caruana11, Angelique Camilleri11, Neville Vassallo11, Markus Zweckstetter4,5,8,12, Roland Benz13, Armin Giese14, Anja Schneider5,6,9, Martin Korte *,7,15, Ratnesh Lal *,3, Christian Griesinger *,4,5, Gregor Eichele *,2 and Andre Fischer *,1,6 1Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany 2Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany 3Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA 4Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany 5DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany 6Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany 7Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany 8Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany 9Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany 10Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 11Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta 12Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany 13Life Sciences and Chemistry, Jacobs University of Bremen, Bremen, Germany 14Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany 15Helmholtz Center for Infections Research, Braunschweig, Germany 16Present address: Departments of Medicine and Biomedical Engineering, University of Arizona, Tucson, AZ, USA ‡These authors contributed equally to this work *Corresponding author. Tel: +49 531 391 3220; E-mail: [email protected] *Corresponding author. Tel: +1 858 822 0384; E-mail: [email protected] *Corresponding author. Tel: +49 551 201 2201; E-mail: [email protected] *Corresponding author. Tel: +49 551 201 2701; E-mail: [email protected] *Corresponding author. Tel: +49 551 3961211; E-mail: [email protected] EMBO Mol Med (2018)10:32-47https://doi.org/10.15252/emmm.201707825 See also: FX Guix & CG Dotti (January 2018) PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract 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. Synopsis Although a substantial amount of data point to a causative role of amyloid beta and Tau pathology in Alzheimer's disease (AD) pathogenesis, no effective therapy has been developed. This study reports that anle138b blocks amyloid beta channels formation and ameliorates disease pathology. Amyloid beta peptides form conducting channels in neuronal membranes. Amyloid beta channels lead to a loss of cellular homeostasis and memory impairment. The small molecule compound anle138b blocks amyloid beta channels and ameliorates disease phenotypes in animal models. The small molecule compound anle138b also reinstates homeostasis in model of Tau-pathology. Introduction Alzheimer's disease (AD) is the most common neurodegenerative disorder causing a severe emotional and economic burden to our societies. Due to increased life expectancies, the number of those afflicted with AD is expected to double by 2025. Despite intensive research, effective therapeutic approaches are still not available. The pathogenesis of AD has been linked to protein aggregation, namely the aggregation of amyloid-beta peptides (Aβ) and tau protein. The accumulation of pathogenic aggregates of Aβ peptides in the brain appears to be a key event in the pathogenesis of AD (Iversen et al, 1995; Tanzi, 2005; Jakob-Roetne & Jacobsen, 2009; Goate & Hardy, 2012), and targeting amyloid pathology still represents a promising therapeutic strategy (Haass & Selkoe, 2007; Sevigny et al, 2016). The precise molecular events that trigger amyloid-induced decline of synaptic plasticity and neuronal cell death are still not entirely resolved and are likely to be multifactorial. One of the first explanations of neuronal dysfunction and toxicity in AD is the channel hypothesis first proposed by Arispe and coworkers (Arispe et al, 1993), which postulates that unregulated Aβ ion channels result in a loss of ionic homeostasis (primarily through a gain of Ca2+) that eventually triggers neuronal dysfunction and cell death. In vivo evidence for this mechanism is, however, still rare, and a compound that would block pores and be active in mammalian animal models has not been reported yet. Thus, the original request by Arispe and coworkers that a useful strategy for drug discovery for treatment of AD should include screening compounds for their ability to block or otherwise modify Aβ channels is still left unsatisfied (Arispe et al, 1993). In this work, we examine the efficacy of the diphenylpyrazole (DPP) compound anle138b in an animal model of Aβ deposition. Oral application of anle138b ameliorates Aβ-induced deficits in synaptic plasticity and memory formation. Using in vivo and in vitro approaches, we provide evidence that this effect is linked to the capacity of anle138b to reduce the conductivity of Aβ pores in lipid bilayer membranes. Although other mechanisms likely contribute to this effect, our data suggest the functional modulation of the membrane bound Aβ-oligomers as a mechanism for neuroprotection and support the idea that anle138b should be taken into clinical trials to treat aggregopathies, including AD. Results Synaptic plasticity and memory function in a mouse model for deposition of amyloid β peptides after oral treatment with anle138b To initially test the potential of anle138b as therapeutic strategies to treat amyloid aggregation in Alzheimer's disease, we analyzed its effect in a Drosophila model for amyloid-induced neurotoxicity. We observed that treatment with anle138b improved survival times when compared to a vehicle-treated group (Appendix Fig S1). On the basis of these data, we decided to test the efficacy of anle138b in a mouse model for amyloid deposition. We like to state that none of the currently employed animal models for AD fully recapitulate the phenotypes seen in AD patients, and thus, care has to be taken when interpreting such data. In our study, we employed APPPS1Δ9 mice (Jankowsky et al, 2001), a well-established model for AD-linked amyloid deposition. Since in the patients therapeutic intervention is normally initiated only after the onset of amyloid plaque formation, we decided to test anle138b in two experimental cohorts. In the "pre-plaque group," treatment was initiated before the onset of pathology when mice were 2 months of age, while in the "post-plaque group" treatment was initiated after the onset of amyloid deposition and memory disturbances in 6-month-old mice (Fig EV1; Jankowsky et al, 2004; Lalonde et al, 2005; Reiserer et al, 2007). In both cohorts, anle138b was continuously provided via food pellets. Thus, in the pre-plaque group, mice were subjected to anle138b or placebo treatment from 2 months of age, and electrophysiological, behavioral, and biochemical analyses were initiated at 6 months of age. A group of wild-type mice (WT) treated with anle138b served as an additional control. We first measured synaptic plasticity by analyzing hippocampal long-term potentiation (LTP). While robust hippocampal LTP at the Schaffer collateral synapse was observed in WT control mice treated with anle138b (Fig 1A), LTP was significantly impaired in APPPS1Δ9 mice that received placebo (Fig 1B). Notably, this LTP deficit was completely rescued in APPPS1Δ9 mice treated with anle138b (Fig 1C). These data suggest that oral application of anle138b protects against Aβ-induced impairment of hippocampal synaptic plasticity. To test whether the effect of anle138b on hippocampal plasticity also improved hippocampus-dependent memory function, another group of anle138b and placebo-treated mice were subjected to the Morris water maze test, a well-established paradigm to assay spatial memory in rodents (Morris, 1984). Anle138b-treated WT mice displayed robust spatial learning as indicated by decreasing escape latency throughout the 8 days of training (Fig 1D). In contrast, APPPS1Δ9 mice treated with placebo showed a significantly impaired escape latency (Fig 1D). This deficit was partially rescued in APPPS1Δ9 mice that received anle138b. Spatial reference memory was analyzed in a probe test performed after 8 days of training. While WT mice showed a significant preference for the target quadrant, no such effect was observed in placebo-treated APPPS1Δ9 mice (Fig 1E), confirming memory impairment in APPPS1Δ9 mice. In contrast, anle138b-treated APPPS1Δ9 mice displayed a significant preference for the target quadrant indicating restored spatial memory (Fig 1E). Swim speed was similar amongst the groups (Fig 1F). We also examined if anle138b would affect basal explorative behavior (Fig 1G) or basal anxiety (Fig 1H). No difference was found amongst the groups suggesting that oral administration of anle138b can protect APPPS1Δ9 mice from deteriorating hippocampal synaptic plasticity and hippocampus-dependent memory consolidation. Click here to expand this figure. Figure EV1. Experimental designOverview of the experimental approach employed for the pre-plaque and the post-plaque group. Red arrows underneath the time line indicate onset of pathology in APPPS1△9 mice. Download figure Download PowerPoint Figure 1. Anle138b rescues hippocampal LTP deficits spatial memory in the pre-plaque group In wild-type mice of the pre-plaque group (treated from 2 to 6 months of age with anle138b), robust LTP that lasts for at least 3 h is elicited upon a strong tetanization (STET) (3 trains of 100 pulses at 100 Hz given 10 min apart, arrows) at the Schaffer collateral CA3-CA1 synapse (t-test, P = 0.00005; n = 16 comparing before vs. after STET). LTP is not maintained in APPPS1Δ9 mice treated with placebo. Here, the potentiation declined to baseline after 3 h (t-test, P = 0.08; n = 20 comparing before vs. after STET). APPPS1Δ9 treated with anle138b show a rescue of the LTP impairment (t-test, P = 0.0001; n = 23 comparing before vs. after STET). Escape latency in the Morris water maze test is impaired in placebo- but not in anle138b-treated APP mice (one-way ANOVA F = 16.01, **P = 0.0008; n = 15/group). Probe test performed 24 h after the last training session. The lower panel shows representative swimming path during the probe test. T = target quadrant compared vs. other quadrants (t-test, ***P = 0.00002; n = 15/group). Average swim speed during water maze training (n = 15/group). Explorative behavior in the open field test. Upper panel: Representative motion tracks during the test session. Lower panels show the total distance travelled during the 5-min test session (n = 15/group). Bar graph showing the time spent in the center vs. the corner of the open field (n = 15/group). Data information: Error bars indicate SEM. Download figure Download PowerPoint Encouraged by these findings, we investigated whether anle138b could also reinstate synaptic plasticity and memory function when significant amyloid deposition had already occurred employing the post-plaque group (Fig EV1). To this end, 6-month-old APPPS1Δ9 mice were treated with either anle138b or placebo for 4 months. Wild-type mice treated with anle138b served as an additional control group. Analysis was performed when mice were 10 months of age. In a first cohort, we measured hippocampal LTP. WT mice treated with anle138b showed robust LTP (Fig 2A), while LTP was significantly impaired in placebo-treated APPPS1Δ9 mice (Fig 2B). Notably, a complete restoration of hippocampal LTP was seen in APPPS1Δ9 mice treated with anle138b (Fig 2C). In conclusion, similar to the pre-plaque group treatment with anle138b had a marked ameliorating effect on LTP even after the onset of plaque deposition. Figure 2. Anle138b rescues hippocampal LTP deficits and spatial memory in the post-plaque group Wild-type mice of the post-plaque group (treated from 6 to 10 months of age) display robust LTP upon STET (arrows) that was maintained throughout the recording session (t-test, P = 0.00006; n = 30 comparing before vs. after STET). Lasting LTP induced by STET was not observed in 10-month-old APPPS1Δ9 placebo-treated mice. The potentiation decayed to baseline after 3 h (t-test, P = 0.16; n = 19 comparing before vs. after STET). Treatment with anle138b starting at 6 months of age rescues LTP deficit in 10-month-old APPPS1Δ9 mice (t-test, P = 0.0003; n = 20 comparing before vs. after STET). Escape latency in the Morris water maze test is impaired in placebo-treated APP mice and partially restored to WT levels in anle138b-treated APP mice (one-way ANOVA, F = 35.94, P = 0.00006; *P = 0.0309 for APP + anle138b vs. APP + placebo and P = 0.4 for APP + placebo vs. WT + anle138b; n = 7/group). Probe test performed 24 h after the last training session. The lower panel shows representative swimming path during the probe test. T = target quadrant compared vs. o
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