Kaichuan Zhu1, Xianyuan Xiang2, Severin Filser1, Petar Marinković3, Mario M Dorostkar1, Sophie Crux1, Ulf Neumann4, Derya R Shimshek4, Gerhard Rammes5, Christian Haass6, Stefan F Lichtenthaler7, Jenny M Gunnersen8, Jochen Herms9. 1. German Center for Neurodegenerative Diseases, Munich, Germany; Center for Neuropathology and Prion Research, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany. 2. Graduate School of Systemic Neuroscience, Ludwig-Maximilians University Munich, Munich, Germany. 3. German Center for Neurodegenerative Diseases, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany. 4. Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. 5. Department of Anesthesiology, Klinikum rechts der Isar, Munich, Germany. 6. German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany. 7. 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. 8. Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia. 9. 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.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. METHODS: 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. RESULTS: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. CONCLUSIONS: 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.
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