TY  - JOUR
AU  - Shi, Dai
AU  - Wong, Jaime K Y
AU  - Zhu, Kaichuan
AU  - Noakes, Peter G
AU  - Rammes, Gerhard
TI  - The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aβ1-42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices.
JO  - International journal of molecular sciences
VL  - 24
IS  - 2
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DZNE-2023-00167
SP  - 912
PY  - 2023
AB  - It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer's disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how β-amyloid peptide 1-42 (Aβ1-42), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aβ1-42, Iso or Xe and the combination of Aβ1-42 with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aβ1-42 elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aβ1-42 both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aβ1-42-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation.
KW  - Mice
KW  - Animals
KW  - Isoflurane: pharmacology
KW  - Xenon: pharmacology
KW  - Xenon: metabolism
KW  - Astrocytes: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Brain: metabolism
KW  - Hippocampus: metabolism
KW  - Peptide Fragments: metabolism
KW  - Alzheimer Disease: metabolism
KW  - Anesthetics, Inhalation: pharmacology
KW  - Synapses: metabolism
KW  - Membrane Proteins: metabolism
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - MEGF10 (Other)
KW  - astrocytes (Other)
KW  - dendritic spine density (Other)
KW  - phagocytosis (Other)
KW  - synapse elimination (Other)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
KW  - Isoflurane (NLM Chemicals)
KW  - Xenon (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Anesthetics, Inhalation (NLM Chemicals)
KW  - Megf10 protein, mouse (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36674434
C2  - pmc:PMC9861496
DO  - DOI:10.3390/ijms24020912
UR  - https://pub.dzne.de/record/194980
ER  -