Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions
| Autor: | Mercè Masana, Marianne B. Müller, Christian K.E. Jung, Lidia Blazquez-Llorca, Christiane Volbracht, Anders Brandt Elvang, Saak V. Ovsepian, Jochen Herms, Severin Filser |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Dendritic spine
Time Factors drug effects [Pyramidal Cells] Thiazines Nonsynaptic plasticity genetics [Amyloid Precursor Protein Secretases] pharmacology [Enzyme Inhibitors] chemically induced [Cognitive Dysfunction] LY2811376 pharmacology [Pyrimidines] metabolism [Cognitive Dysfunction] Mice Cognition pharmacology [Thiazines] Amyloid precursor protein metabolism [Peptide Fragments] pharmacology [Thiophenes] Aspartic Acid Endopeptidases Enzyme Inhibitors chemistry [Enzyme Inhibitors] biology physiology [Pyramidal Cells] drug effects [Exploratory Behavior] Pyramidal Cells physiology [Cognition] Brain Long-term potentiation chemistry [Pyrimidines] Synaptic Potentials deficiency [Amyloid Precursor Protein Secretases] Excitatory postsynaptic potential drug effects [Brain] physiology [Synaptic Potentials] Dendritic Spines Bace1 protein mouse metabolism [Amyloid beta-Peptides] Mice Transgenic pharmacology [Pyrimidinones] chemistry [Thiazines] Pyrimidinones Thiophenes Neurotransmission drug effects [Maze Learning] SCH1682496 Synaptic augmentation mental disorders drug effects [Synaptic Potentials] Animals Humans Cognitive Dysfunction ddc:610 Maze Learning Biological Psychiatry deficiency [Aspartic Acid Endopeptidases] drug effects [Dendritic Spines] Amyloid beta-Peptides Dose-Response Relationship Drug amyloid beta-protein (1-40) Peptide Fragments Mice Inbred C57BL Pyrimidines metabolism [Dendritic Spines] genetics [Aspartic Acid Endopeptidases] metabolism [Brain] Synaptic plasticity Exploratory Behavior biology.protein Amyloid Precursor Protein Secretases Neuroscience anatomy & histology [Brain] |
| Zdroj: | Biological psychiatry 77(8), 729-739 (2015). doi:10.1016/j.biopsych.2014.10.013 |
| DOI: | 10.1016/j.biopsych.2014.10.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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