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@ARTICLE{Filser:137858,
      author       = {Filser, Severin and Ovsepian, Saak V and Masana, Mercè and
                      Blazquez-Llorca, Lidia and Brandt Elvang, Anders and
                      Volbracht, Christiane and Müller, Marianne B and Jung,
                      Christian K E and Herms, Jochen},
      title        = {{P}harmacological inhibition of {BACE}1 impairs synaptic
                      plasticity and cognitive functions.},
      journal      = {Biological psychiatry},
      volume       = {77},
      number       = {8},
      issn         = {0006-3223},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DZNE-2020-04180},
      pages        = {729-739},
      year         = {2015},
      abstract     = {BACE1 (beta site amyloid precursor protein cleaving enzyme
                      1) is the rate limiting protease in amyloid β production,
                      hence a promising drug target for the treatment of
                      Alzheimer's disease. Inhibition of BACE1, as the major
                      β-secretase in vivo with multiple substrates, however is
                      likely to have mechanism-based adverse effects. We explored
                      the impact of long-term pharmacological inhibition of BACE1
                      on dendritic spine dynamics, synaptic functions, and
                      cognitive performance of adult mice.Sandwich enzyme-linked
                      immunosorbent assay was used to assess Aβ40 levels in brain
                      and plasma after oral administration of BACE1 inhibitors
                      SCH1682496 or LY2811376. In vivo two-photon microscopy of
                      the somatosensory cortex was performed to monitor structural
                      dynamics of dendritic spines while synaptic functions and
                      plasticity were measured via electrophysiological recordings
                      of excitatory postsynaptic currents and hippocampal
                      long-term potentiation in brain slices. Finally, behavioral
                      tests were performed to analyze the impact of
                      pharmacological inhibition of BACE1 on cognitive
                      performance.Dose-dependent decrease of Aβ40 levels in vivo
                      confirmed suppression of BACE1 activity by both inhibitors.
                      Prolonged treatment caused a reduction in spine formation of
                      layer V pyramidal neurons, which recovered after withdrawal
                      of inhibitors. Congruently, the rate of spontaneous and
                      miniature excitatory postsynaptic currents in pyramidal
                      neurons and hippocampal long-term potentiation were reduced
                      in animals treated with BACE1 inhibitors. These effects were
                      not detected in Bace1(-/-) mice treated with SCH1682496,
                      confirming BACE1 as the pharmacological target. Described
                      structural and functional changes were associated with
                      cognitive deficits as revealed in behavioral tests.Our
                      findings indicate important functions to BACE1 in structural
                      and functional synaptic plasticity in the mature brain, with
                      implications for cognition.},
      keywords     = {Amyloid Precursor Protein Secretases: deficiency / Amyloid
                      Precursor Protein Secretases: genetics / Amyloid
                      beta-Peptides: metabolism / Animals / Aspartic Acid
                      Endopeptidases: deficiency / Aspartic Acid Endopeptidases:
                      genetics / Brain: anatomy $\&$ histology / Brain: drug
                      effects / Brain: metabolism / Cognition: physiology /
                      Cognitive Dysfunction: chemically induced / Cognitive
                      Dysfunction: metabolism / Dendritic Spines: drug effects /
                      Dendritic Spines: metabolism / Dose-Response Relationship,
                      Drug / Enzyme Inhibitors: chemistry / Enzyme Inhibitors:
                      pharmacology / Exploratory Behavior: drug effects / Humans /
                      Maze Learning: drug effects / Mice / Mice, Inbred C57BL /
                      Mice, Transgenic / Peptide Fragments: metabolism / Pyramidal
                      Cells: drug effects / Pyramidal Cells: physiology /
                      Pyrimidines: chemistry / Pyrimidines: pharmacology /
                      Pyrimidinones: pharmacology / Synaptic Potentials: drug
                      effects / Synaptic Potentials: physiology / Thiazines:
                      chemistry / Thiazines: pharmacology / Thiophenes:
                      pharmacology / Time Factors / Amyloid beta-Peptides (NLM
                      Chemicals) / Enzyme Inhibitors (NLM Chemicals) / LY2811376
                      (NLM Chemicals) / Peptide Fragments (NLM Chemicals) /
                      Pyrimidines (NLM Chemicals) / Pyrimidinones (NLM Chemicals)
                      / SCH1682496 (NLM Chemicals) / Thiazines (NLM Chemicals) /
                      Thiophenes (NLM Chemicals) / amyloid beta-protein (1-40)
                      (NLM Chemicals) / Amyloid Precursor Protein Secretases (NLM
                      Chemicals) / Aspartic Acid Endopeptidases (NLM Chemicals) /
                      Bace1 protein, mouse (NLM Chemicals)},
      cin          = {AG Herms},
      ddc          = {610},
      cid          = {I:(DE-2719)1110001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25599931},
      doi          = {10.1016/j.biopsych.2014.10.013},
      url          = {https://pub.dzne.de/record/137858},
}