Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage
Abstract Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aβ. Although m...
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2014
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00283908_v79_n_p180_Durand http://hdl.handle.net/20.500.12110/paper_00283908_v79_n_p180_Durand |
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paper:paper_00283908_v79_n_p180_Durand2023-06-08T14:55:10Z Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage Amyloid precursor protein Astrocytes Hippocampus Keywords Metabotropic glutamate receptor 3 PDAPP-J20 mice Secretases ADAM protein ADAM10 endopeptidase alpha secretase amyloid precursor protein beta secretase metabotropic receptor 2 metabotropic receptor 3 peroxisome proliferator activated receptor gamma protein ADAM17 unclassified drug 4 amino 2 oxabicyclo[3.1.0]hexane 4,6 dicarboxylic acid amino acid amino acid receptor stimulating agent amyloid precursor protein APP protein, human fused heterocyclic rings metabotropic receptor metabotropic receptor 3 secretase Alzheimer disease animal cell animal experiment animal model animal tissue article astrocyte controlled study enzyme activation enzyme release female molecular pathology mouse nonhuman nucleotide sequence priority journal protein cleavage protein expression protein function rat receptor upregulation aging agonists animal C57BL mouse cell culture drug effects genetics hippocampus human metabolism mutation transgenic mouse Wistar rat Aging Amino Acids Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Astrocytes Bicyclo Compounds, Heterocyclic Cells, Cultured Excitatory Amino Acid Agonists Female Hippocampus Humans Mice Mice, Inbred C57BL Mice, Transgenic Mutation Rats Rats, Wistar Receptors, Metabotropic Glutamate Abstract Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aβ. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPα production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPα release from cultured astrocytes by inducing α-secretases expression, whereas it decreased β-secretase levels. LY379268-induced increase of PPAR-γ levels could be involved in the effect of the agonist on sAPPα release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes. © 2013 Elsevier Ltd. All rights reserved. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00283908_v79_n_p180_Durand http://hdl.handle.net/20.500.12110/paper_00283908_v79_n_p180_Durand |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Amyloid precursor protein Astrocytes Hippocampus Keywords Metabotropic glutamate receptor 3 PDAPP-J20 mice Secretases ADAM protein ADAM10 endopeptidase alpha secretase amyloid precursor protein beta secretase metabotropic receptor 2 metabotropic receptor 3 peroxisome proliferator activated receptor gamma protein ADAM17 unclassified drug 4 amino 2 oxabicyclo[3.1.0]hexane 4,6 dicarboxylic acid amino acid amino acid receptor stimulating agent amyloid precursor protein APP protein, human fused heterocyclic rings metabotropic receptor metabotropic receptor 3 secretase Alzheimer disease animal cell animal experiment animal model animal tissue article astrocyte controlled study enzyme activation enzyme release female molecular pathology mouse nonhuman nucleotide sequence priority journal protein cleavage protein expression protein function rat receptor upregulation aging agonists animal C57BL mouse cell culture drug effects genetics hippocampus human metabolism mutation transgenic mouse Wistar rat Aging Amino Acids Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Astrocytes Bicyclo Compounds, Heterocyclic Cells, Cultured Excitatory Amino Acid Agonists Female Hippocampus Humans Mice Mice, Inbred C57BL Mice, Transgenic Mutation Rats Rats, Wistar Receptors, Metabotropic Glutamate |
| spellingShingle |
Amyloid precursor protein Astrocytes Hippocampus Keywords Metabotropic glutamate receptor 3 PDAPP-J20 mice Secretases ADAM protein ADAM10 endopeptidase alpha secretase amyloid precursor protein beta secretase metabotropic receptor 2 metabotropic receptor 3 peroxisome proliferator activated receptor gamma protein ADAM17 unclassified drug 4 amino 2 oxabicyclo[3.1.0]hexane 4,6 dicarboxylic acid amino acid amino acid receptor stimulating agent amyloid precursor protein APP protein, human fused heterocyclic rings metabotropic receptor metabotropic receptor 3 secretase Alzheimer disease animal cell animal experiment animal model animal tissue article astrocyte controlled study enzyme activation enzyme release female molecular pathology mouse nonhuman nucleotide sequence priority journal protein cleavage protein expression protein function rat receptor upregulation aging agonists animal C57BL mouse cell culture drug effects genetics hippocampus human metabolism mutation transgenic mouse Wistar rat Aging Amino Acids Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Astrocytes Bicyclo Compounds, Heterocyclic Cells, Cultured Excitatory Amino Acid Agonists Female Hippocampus Humans Mice Mice, Inbred C57BL Mice, Transgenic Mutation Rats Rats, Wistar Receptors, Metabotropic Glutamate Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| topic_facet |
Amyloid precursor protein Astrocytes Hippocampus Keywords Metabotropic glutamate receptor 3 PDAPP-J20 mice Secretases ADAM protein ADAM10 endopeptidase alpha secretase amyloid precursor protein beta secretase metabotropic receptor 2 metabotropic receptor 3 peroxisome proliferator activated receptor gamma protein ADAM17 unclassified drug 4 amino 2 oxabicyclo[3.1.0]hexane 4,6 dicarboxylic acid amino acid amino acid receptor stimulating agent amyloid precursor protein APP protein, human fused heterocyclic rings metabotropic receptor metabotropic receptor 3 secretase Alzheimer disease animal cell animal experiment animal model animal tissue article astrocyte controlled study enzyme activation enzyme release female molecular pathology mouse nonhuman nucleotide sequence priority journal protein cleavage protein expression protein function rat receptor upregulation aging agonists animal C57BL mouse cell culture drug effects genetics hippocampus human metabolism mutation transgenic mouse Wistar rat Aging Amino Acids Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Astrocytes Bicyclo Compounds, Heterocyclic Cells, Cultured Excitatory Amino Acid Agonists Female Hippocampus Humans Mice Mice, Inbred C57BL Mice, Transgenic Mutation Rats Rats, Wistar Receptors, Metabotropic Glutamate |
| description |
Abstract Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aβ. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPα production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPα release from cultured astrocytes by inducing α-secretases expression, whereas it decreased β-secretase levels. LY379268-induced increase of PPAR-γ levels could be involved in the effect of the agonist on sAPPα release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes. © 2013 Elsevier Ltd. All rights reserved. |
| title |
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| title_short |
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| title_full |
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| title_fullStr |
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| title_full_unstemmed |
Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| title_sort |
astroglial mglu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00283908_v79_n_p180_Durand http://hdl.handle.net/20.500.12110/paper_00283908_v79_n_p180_Durand |
| _version_ |
1768542929007149056 |