Severin Filser1, Saak V Ovsepian2, Mercè Masana3, Lidia Blazquez-Llorca4, Anders Brandt Elvang5, Christiane Volbracht5, Marianne B Müller3, Christian K E Jung6, Jochen Herms7. 1. German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany; Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany. 2. German Center for Neurodegenerative Diseases, Ludwig Maximilian University Munich, Munich, Germany. 3. Max Planck Institute of Psychiatry, Munich, Germany. 4. 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. 5. Department of Neurodegeneration DK, H. Lundbeck A/S, Valby, Denmark. 6. Center for Neuropathology, Ludwig Maximilian University Munich, Munich, Germany. 7. 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.
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.
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: Michael F Egan; James Kost; Tiffini Voss; Yuki Mukai; Paul S Aisen; Jeffrey L Cummings; Pierre N Tariot; Bruno Vellas; Christopher H van Dyck; Merce Boada; Ying Zhang; Wen Li; Christine Furtek; Erin Mahoney; Lyn Harper Mozley; Yi Mo; Cyrille Sur; David Michelson Journal: N Engl J Med Date: 2019-04-11 Impact factor: 91.245
Authors: William J Netzer; Karima Bettayeb; Subhash C Sinha; Marc Flajolet; Paul Greengard; Victor Bustos Journal: Proc Natl Acad Sci U S A Date: 2017-01-23 Impact factor: 11.205