Home > Publications Database > Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. > print

001     137858
005     20240321220328.0
024 7 _ |a 10.1016/j.biopsych.2014.10.013
|2 doi
024 7 _ |a pmid:25599931
|2 pmid
024 7 _ |a 0006-3223
|2 ISSN
024 7 _ |a 1873-2402
|2 ISSN
024 7 _ |a altmetric:2822775
|2 altmetric
037 _ _ |a DZNE-2020-04180
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Filser, Severin
|0 P:(DE-2719)2810523
|b 0
|e First author
|u dzne
245 _ _ |a Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions.
260 _ _ |a Amsterdam [u.a.]
|c 2015
|b Elsevier Science
264 _ 1 |3 print
|2 Crossref
|b Elsevier BV
|c 2015-04-01
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1706091927_14282
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336 7 _ |a ARTICLE
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336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a 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.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.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.Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
|0 G:(DE-HGF)POF3-342
|c POF3-342
|f POF III
|x 0
542 _ _ |i 2015-04-01
|2 Crossref
|u https://www.elsevier.com/tdm/userlicense/1.0/
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Enzyme Inhibitors
|2 NLM Chemicals
650 _ 7 |a LY2811376
|2 NLM Chemicals
650 _ 7 |a Peptide Fragments
|2 NLM Chemicals
650 _ 7 |a Pyrimidines
|2 NLM Chemicals
650 _ 7 |a Pyrimidinones
|2 NLM Chemicals
650 _ 7 |a SCH1682496
|2 NLM Chemicals
650 _ 7 |a Thiazines
|2 NLM Chemicals
650 _ 7 |a Thiophenes
|2 NLM Chemicals
650 _ 7 |a amyloid beta-protein (1-40)
|2 NLM Chemicals
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Aspartic Acid Endopeptidases
|0 EC 3.4.23.-
|2 NLM Chemicals
650 _ 7 |a Bace1 protein, mouse
|0 EC 3.4.23.46
|2 NLM Chemicals
650 _ 2 |a Amyloid Precursor Protein Secretases: deficiency
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: deficiency
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: genetics
|2 MeSH
650 _ 2 |a Brain: anatomy & histology
|2 MeSH
650 _ 2 |a Brain: drug effects
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Cognition: physiology
|2 MeSH
650 _ 2 |a Cognitive Dysfunction: chemically induced
|2 MeSH
650 _ 2 |a Cognitive Dysfunction: metabolism
|2 MeSH
650 _ 2 |a Dendritic Spines: drug effects
|2 MeSH
650 _ 2 |a Dendritic Spines: metabolism
|2 MeSH
650 _ 2 |a Dose-Response Relationship, Drug
|2 MeSH
650 _ 2 |a Enzyme Inhibitors: chemistry
|2 MeSH
650 _ 2 |a Enzyme Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Exploratory Behavior: drug effects
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Maze Learning: drug effects
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Peptide Fragments: metabolism
|2 MeSH
650 _ 2 |a Pyramidal Cells: drug effects
|2 MeSH
650 _ 2 |a Pyramidal Cells: physiology
|2 MeSH
650 _ 2 |a Pyrimidines: chemistry
|2 MeSH
650 _ 2 |a Pyrimidines: pharmacology
|2 MeSH
650 _ 2 |a Pyrimidinones: pharmacology
|2 MeSH
650 _ 2 |a Synaptic Potentials: drug effects
|2 MeSH
650 _ 2 |a Synaptic Potentials: physiology
|2 MeSH
650 _ 2 |a Thiazines: chemistry
|2 MeSH
650 _ 2 |a Thiazines: pharmacology
|2 MeSH
650 _ 2 |a Thiophenes: pharmacology
|2 MeSH
650 _ 2 |a Time Factors
|2 MeSH
700 1 _ |a Ovsepian, Saak V
|0 P:(DE-2719)9000407
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|u dzne
700 1 _ |a Masana, Mercè
|b 2
700 1 _ |a Blazquez-Llorca, Lidia
|0 P:(DE-2719)2812990
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700 1 _ |a Brandt Elvang, Anders
|b 4
700 1 _ |a Volbracht, Christiane
|b 5
700 1 _ |a Müller, Marianne B
|b 6
700 1 _ |a Jung, Christian K E
|0 P:(DE-HGF)0
|b 7
700 1 _ |a Herms, Jochen
|0 P:(DE-2719)2810441
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|e Last author
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773 1 8 |a 10.1016/j.biopsych.2014.10.013
|b : Elsevier BV, 2015-04-01
|n 8
|p 729-739
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|t Biological Psychiatry
|v 77
|y 2015
|x 0006-3223
773 _ _ |a 10.1016/j.biopsych.2014.10.013
|g Vol. 77, no. 8, p. 729 - 739
|0 PERI:(DE-600)1499907-9
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|q 77:8<729 - 739
|p 729-739
|t Biological psychiatry
|v 77
|y 2015
|x 0006-3223
856 4 _ |u https://pub.dzne.de/record/137858/files/DZNE-2020-04180_Restricted.pdf
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