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000137858 0247_ $$2doi$$a10.1016/j.biopsych.2014.10.013
000137858 0247_ $$2pmid$$apmid:25599931
000137858 0247_ $$2ISSN$$a0006-3223
000137858 0247_ $$2ISSN$$a1873-2402
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000137858 037__ $$aDZNE-2020-04180
000137858 041__ $$aEnglish
000137858 082__ $$a610
000137858 1001_ $$0P:(DE-2719)2810523$$aFilser, Severin$$b0$$eFirst author$$udzne
000137858 245__ $$aPharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions.
000137858 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2015
000137858 264_1 $$2Crossref$$3print$$bElsevier BV$$c2015-04-01
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000137858 520__ $$aBACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects. We explored the impact of long-term pharmacological inhibition of BACE1 on dendritic spine dynamics, synaptic functions, and cognitive performance of adult mice.Sandwich enzyme-linked immunosorbent assay was used to assess Aβ40 levels in brain and plasma after oral administration of BACE1 inhibitors SCH1682496 or LY2811376. In vivo two-photon microscopy of the somatosensory cortex was performed to monitor structural dynamics of dendritic spines while synaptic functions and plasticity were measured via electrophysiological recordings of excitatory postsynaptic currents and hippocampal long-term potentiation in brain slices. Finally, behavioral tests were performed to analyze the impact of pharmacological inhibition of BACE1 on cognitive performance.Dose-dependent decrease of Aβ40 levels in vivo confirmed suppression of BACE1 activity by both inhibitors. Prolonged treatment caused a reduction in spine formation of layer V pyramidal neurons, which recovered after withdrawal of inhibitors. Congruently, the rate of spontaneous and miniature excitatory postsynaptic currents in pyramidal neurons and hippocampal long-term potentiation were reduced in animals treated with BACE1 inhibitors. These effects were not detected in Bace1(-/-) mice treated with SCH1682496, confirming BACE1 as the pharmacological target. Described structural and functional changes were associated with cognitive deficits as revealed in behavioral tests.Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.
000137858 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000137858 542__ $$2Crossref$$i2015-04-01$$uhttps://www.elsevier.com/tdm/userlicense/1.0/
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000137858 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000137858 650_7 $$2NLM Chemicals$$aEnzyme Inhibitors
000137858 650_7 $$2NLM Chemicals$$aLY2811376
000137858 650_7 $$2NLM Chemicals$$aPeptide Fragments
000137858 650_7 $$2NLM Chemicals$$aPyrimidines
000137858 650_7 $$2NLM Chemicals$$aPyrimidinones
000137858 650_7 $$2NLM Chemicals$$aSCH1682496
000137858 650_7 $$2NLM Chemicals$$aThiazines
000137858 650_7 $$2NLM Chemicals$$aThiophenes
000137858 650_7 $$2NLM Chemicals$$aamyloid beta-protein (1-40)
000137858 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000137858 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000137858 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBace1 protein, mouse
000137858 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: deficiency
000137858 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000137858 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000137858 650_2 $$2MeSH$$aAnimals
000137858 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: deficiency
000137858 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000137858 650_2 $$2MeSH$$aBrain: anatomy & histology
000137858 650_2 $$2MeSH$$aBrain: drug effects
000137858 650_2 $$2MeSH$$aBrain: metabolism
000137858 650_2 $$2MeSH$$aCognition: physiology
000137858 650_2 $$2MeSH$$aCognitive Dysfunction: chemically induced
000137858 650_2 $$2MeSH$$aCognitive Dysfunction: metabolism
000137858 650_2 $$2MeSH$$aDendritic Spines: drug effects
000137858 650_2 $$2MeSH$$aDendritic Spines: metabolism
000137858 650_2 $$2MeSH$$aDose-Response Relationship, Drug
000137858 650_2 $$2MeSH$$aEnzyme Inhibitors: chemistry
000137858 650_2 $$2MeSH$$aEnzyme Inhibitors: pharmacology
000137858 650_2 $$2MeSH$$aExploratory Behavior: drug effects
000137858 650_2 $$2MeSH$$aHumans
000137858 650_2 $$2MeSH$$aMaze Learning: drug effects
000137858 650_2 $$2MeSH$$aMice
000137858 650_2 $$2MeSH$$aMice, Inbred C57BL
000137858 650_2 $$2MeSH$$aMice, Transgenic
000137858 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000137858 650_2 $$2MeSH$$aPyramidal Cells: drug effects
000137858 650_2 $$2MeSH$$aPyramidal Cells: physiology
000137858 650_2 $$2MeSH$$aPyrimidines: chemistry
000137858 650_2 $$2MeSH$$aPyrimidines: pharmacology
000137858 650_2 $$2MeSH$$aPyrimidinones: pharmacology
000137858 650_2 $$2MeSH$$aSynaptic Potentials: drug effects
000137858 650_2 $$2MeSH$$aSynaptic Potentials: physiology
000137858 650_2 $$2MeSH$$aThiazines: chemistry
000137858 650_2 $$2MeSH$$aThiazines: pharmacology
000137858 650_2 $$2MeSH$$aThiophenes: pharmacology
000137858 650_2 $$2MeSH$$aTime Factors
000137858 7001_ $$0P:(DE-2719)9000407$$aOvsepian, Saak V$$b1$$udzne
000137858 7001_ $$aMasana, Mercè$$b2
000137858 7001_ $$0P:(DE-2719)2812990$$aBlazquez-Llorca, Lidia$$b3$$udzne
000137858 7001_ $$aBrandt Elvang, Anders$$b4
000137858 7001_ $$aVolbracht, Christiane$$b5
000137858 7001_ $$aMüller, Marianne B$$b6
000137858 7001_ $$0P:(DE-HGF)0$$aJung, Christian K E$$b7
000137858 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b8$$eLast author$$udzne
000137858 77318 $$2Crossref$$3journal-article$$a10.1016/j.biopsych.2014.10.013$$b : Elsevier BV, 2015-04-01$$n8$$p729-739$$tBiological Psychiatry$$v77$$x0006-3223$$y2015
000137858 773__ $$0PERI:(DE-600)1499907-9$$a10.1016/j.biopsych.2014.10.013$$gVol. 77, no. 8, p. 729 - 739$$n8$$p729-739$$q77:8<729 - 739$$tBiological psychiatry$$v77$$x0006-3223$$y2015
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