title: Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.
authors.affiliation: German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany; Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: Severin
authors.initials: S
authors.lastname: Filser
authors.affiliation: German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: Saak V
authors.initials: SV
authors.lastname: Ovsepian
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Mercè
authors.initials: M
authors.lastname: Masana
authors.affiliation: German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany; Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: Lidia
authors.initials: L
authors.lastname: Blazquez-Llorca
authors.affiliation: Department of Neurodegeneration DK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Brandt Elvang
authors.affiliation: Department of Neurodegeneration DK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Christiane
authors.initials: C
authors.lastname: Volbracht
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Müller
authors.affiliation: Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: Christian K E
authors.initials: CK
authors.lastname: Jung
authors.affiliation: German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany; Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University Munich, Munich, Germany. Electronic address: Jochen.Herms@med.uni-muenchen.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology*; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C569204:LY2811376; D010446:Peptide Fragments; D011743:Pyrimidines; D011744:Pyrimidinones; C000603951:SCH1682496; D013843:Thiazines; D013876:Thiophenes; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer’s disease; BACE1; Dendritic spines; In vivo two-photon imaging; Learning and memory; Long-term potentiation; Synaptic transmission