TY  - JOUR
AU  - Filser, Severin
AU  - Ovsepian, Saak V
AU  - Masana, Mercè
AU  - Blazquez-Llorca, Lidia
AU  - Brandt Elvang, Anders
AU  - Volbracht, Christiane
AU  - Müller, Marianne B
AU  - Jung, Christian K E
AU  - Herms, Jochen
TI  - Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions.
JO  - Biological psychiatry
VL  - 77
IS  - 8
SN  - 0006-3223
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DZNE-2020-04180
SP  - 729-739
PY  - 2015
AB  - 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.
KW  - Amyloid Precursor Protein Secretases: deficiency
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Animals
KW  - Aspartic Acid Endopeptidases: deficiency
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Brain: anatomy & histology
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Cognition: physiology
KW  - Cognitive Dysfunction: chemically induced
KW  - Cognitive Dysfunction: metabolism
KW  - Dendritic Spines: drug effects
KW  - Dendritic Spines: metabolism
KW  - Dose-Response Relationship, Drug
KW  - Enzyme Inhibitors: chemistry
KW  - Enzyme Inhibitors: pharmacology
KW  - Exploratory Behavior: drug effects
KW  - Humans
KW  - Maze Learning: drug effects
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Peptide Fragments: metabolism
KW  - Pyramidal Cells: drug effects
KW  - Pyramidal Cells: physiology
KW  - Pyrimidines: chemistry
KW  - Pyrimidines: pharmacology
KW  - Pyrimidinones: pharmacology
KW  - Synaptic Potentials: drug effects
KW  - Synaptic Potentials: physiology
KW  - Thiazines: chemistry
KW  - Thiazines: pharmacology
KW  - Thiophenes: pharmacology
KW  - Time Factors
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - LY2811376 (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - Pyrimidinones (NLM Chemicals)
KW  - SCH1682496 (NLM Chemicals)
KW  - Thiazines (NLM Chemicals)
KW  - Thiophenes (NLM Chemicals)
KW  - amyloid beta-protein (1-40) (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - Bace1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25599931
DO  - DOI:10.1016/j.biopsych.2014.10.013
UR  - https://pub.dzne.de/record/137858
ER  -