title: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6.
abstract: Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a promising drug target for the treatment of Alzheimer's disease. Prolonged BACE1 inhibition interferes with structural and functional synaptic plasticity in mice, most likely by altering the metabolism of BACE1 substrates. Seizure protein 6 (SEZ6) is predominantly cleaved by BACE1, and Sez6 knockout mice share some phenotypes with BACE1 inhibitor-treated mice. We investigated whether SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations.
  
  
  
  The function of NB-360, a novel blood-brain barrier penetrant and orally available BACE1 inhibitor, was verified by immunoblotting. In vivo microscopy was applied to monitor the impact of long-term pharmacological BACE1 inhibition on dendritic spines in the cerebral cortex of constitutive and conditional Sez6 knockout mice. Finally, synaptic functions were characterized using electrophysiological field recordings in hippocampal slices.
  
  
  
  BACE1 enzymatic activity was strongly suppressed by NB-360. Prolonged NB-360 treatment caused a reversible spine density reduction in wild-type mice, but it did not affect Sez6-/-mice. Knocking out Sez6 in a small subset of mature neurons also prevented the structural postsynaptic changes induced by BACE1 inhibition. Hippocampal long-term potentiation was decreased in both chronic BACE1 inhibitor-treated wild-type mice and vehicle-treated Sez6-/-mice. However, chronic NB-360 treatment did not alter long-term potentiation in CA1 neurons of Sez6-/-mice.
  
  
  
  Our results suggest that SEZ6 plays an important role in maintaining normal dendritic spine dynamics. Furthermore, SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations.
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Kaichuan
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Graduate School of Systemic Neuroscience, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Xianyuan
authors.initials: X
authors.lastname: Xiang
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Severin
authors.initials: S
authors.lastname: Filser
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Petar
authors.initials: P
authors.lastname: Marinković
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Crux
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.affiliation: Department of Anesthesiology, Klinikum rechts der Isar, Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rammes
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany; Institute for Advanced Study, Technical University of Munich, Munich, Germany; Neuroproteomics, Klinikum rechts der Isar, Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Gunnersen
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, 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 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; C093131:Sez6 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer’s disease; BACE1 inhibition; Dendritic spines; In vivo two-photon imaging; Long-term potentiation; Sez6