Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease
Abstract Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neu...
Published in: | Translational Psychiatry |
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2023
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Online Access: | https://doi.org/10.1038/s41398-023-02630-z https://doaj.org/article/9bce5b1e25554b58a97d1c9a9a70e46d |
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ftdoajarticles:oai:doaj.org/article:9bce5b1e25554b58a97d1c9a9a70e46d 2023-12-03T10:17:29+01:00 Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease Arpit Kumar Pradhan Tatjana Neumüller Claudia Klug Severin Fuchs Martin Schlegel Markus Ballmann Katharina Johanna Tartler Antoine Pianos Maria Sanchez Garcia Philippe Liere Michael Schumacher Matthias Kreuzer Rainer Rupprecht Gerhard Rammes 2023-10-01T00:00:00Z https://doi.org/10.1038/s41398-023-02630-z https://doaj.org/article/9bce5b1e25554b58a97d1c9a9a70e46d EN eng Nature Publishing Group https://doi.org/10.1038/s41398-023-02630-z https://doaj.org/toc/2158-3188 doi:10.1038/s41398-023-02630-z 2158-3188 https://doaj.org/article/9bce5b1e25554b58a97d1c9a9a70e46d Translational Psychiatry, Vol 13, Iss 1, Pp 1-20 (2023) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 article 2023 ftdoajarticles https://doi.org/10.1038/s41398-023-02630-z 2023-11-05T01:44:05Z Abstract Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Translational Psychiatry 13 1 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 |
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Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Arpit Kumar Pradhan Tatjana Neumüller Claudia Klug Severin Fuchs Martin Schlegel Markus Ballmann Katharina Johanna Tartler Antoine Pianos Maria Sanchez Garcia Philippe Liere Michael Schumacher Matthias Kreuzer Rainer Rupprecht Gerhard Rammes Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
topic_facet |
Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 |
description |
Abstract Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD. |
format |
Article in Journal/Newspaper |
author |
Arpit Kumar Pradhan Tatjana Neumüller Claudia Klug Severin Fuchs Martin Schlegel Markus Ballmann Katharina Johanna Tartler Antoine Pianos Maria Sanchez Garcia Philippe Liere Michael Schumacher Matthias Kreuzer Rainer Rupprecht Gerhard Rammes |
author_facet |
Arpit Kumar Pradhan Tatjana Neumüller Claudia Klug Severin Fuchs Martin Schlegel Markus Ballmann Katharina Johanna Tartler Antoine Pianos Maria Sanchez Garcia Philippe Liere Michael Schumacher Matthias Kreuzer Rainer Rupprecht Gerhard Rammes |
author_sort |
Arpit Kumar Pradhan |
title |
Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
title_short |
Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
title_full |
Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
title_fullStr |
Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
title_full_unstemmed |
Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease |
title_sort |
chronic administration of xbd173 ameliorates cognitive deficits and neuropathology via 18 kda translocator protein (tspo) in a mouse model of alzheimer’s disease |
publisher |
Nature Publishing Group |
publishDate |
2023 |
url |
https://doi.org/10.1038/s41398-023-02630-z https://doaj.org/article/9bce5b1e25554b58a97d1c9a9a70e46d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Translational Psychiatry, Vol 13, Iss 1, Pp 1-20 (2023) |
op_relation |
https://doi.org/10.1038/s41398-023-02630-z https://doaj.org/toc/2158-3188 doi:10.1038/s41398-023-02630-z 2158-3188 https://doaj.org/article/9bce5b1e25554b58a97d1c9a9a70e46d |
op_doi |
https://doi.org/10.1038/s41398-023-02630-z |
container_title |
Translational Psychiatry |
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13 |
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1 |
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1784264440104878080 |