Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPP&...

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Autores principales:	Estibaliz González de San Román, Alberto Llorente-Ovejero, Jonatan Martínez-Gardeazabal, Marta Moreno-Rodríguez, Lydia Giménez-Llort, Iván Manuel, Rafael Rodríguez-Puertas
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Alzheimer’s disease functional autoradiography cannabinoid receptors LPA receptors sphingosine 1-phosphate ligand binding Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/74df66c978ad4466922187f854e95fa9
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spelling	oai:doaj.org-article:74df66c978ad4466922187f854e95fa92021-11-25T17:54:53ZModulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease10.3390/ijms2222122561422-00671661-6596https://doaj.org/article/74df66c978ad4466922187f854e95fa92021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12256https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPP<sub>Swe</sub>, PS1<sub>M146V</sub>, and tau<sub>P301L</sub> transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [<sup>35</sup>S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB<sub>1</sub>, LPA<sub>1</sub>, and S1P<sub>1</sub> G<sub>i/0</sub> coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB<sub>1</sub> receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA<sub>1</sub> activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P<sub>1</sub> activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.Estibaliz González de San RománAlberto Llorente-OvejeroJonatan Martínez-GardeazabalMarta Moreno-RodríguezLydia Giménez-LlortIván ManuelRafael Rodríguez-PuertasMDPI AGarticleAlzheimer’s diseasefunctional autoradiographycannabinoid receptorsLPA receptorssphingosine 1-phosphateligand bindingBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12256, p 12256 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease functional autoradiography cannabinoid receptors LPA receptors sphingosine 1-phosphate ligand binding Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Alzheimer’s disease functional autoradiography cannabinoid receptors LPA receptors sphingosine 1-phosphate ligand binding Biology (General) QH301-705.5 Chemistry QD1-999 Estibaliz González de San Román Alberto Llorente-Ovejero Jonatan Martínez-Gardeazabal Marta Moreno-Rodríguez Lydia Giménez-Llort Iván Manuel Rafael Rodríguez-Puertas Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
description	Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPP<sub>Swe</sub>, PS1<sub>M146V</sub>, and tau<sub>P301L</sub> transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [<sup>35</sup>S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB<sub>1</sub>, LPA<sub>1</sub>, and S1P<sub>1</sub> G<sub>i/0</sub> coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB<sub>1</sub> receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA<sub>1</sub> activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P<sub>1</sub> activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.
format	article
author	Estibaliz González de San Román Alberto Llorente-Ovejero Jonatan Martínez-Gardeazabal Marta Moreno-Rodríguez Lydia Giménez-Llort Iván Manuel Rafael Rodríguez-Puertas
author_facet	Estibaliz González de San Román Alberto Llorente-Ovejero Jonatan Martínez-Gardeazabal Marta Moreno-Rodríguez Lydia Giménez-Llort Iván Manuel Rafael Rodríguez-Puertas
author_sort	Estibaliz González de San Román
title	Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
title_short	Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
title_full	Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
title_fullStr	Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
title_full_unstemmed	Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease
title_sort	modulation of neurolipid signaling and specific lipid species in the triple transgenic mouse model of alzheimer’s disease
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/74df66c978ad4466922187f854e95fa9
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Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

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