Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization
<div><p>In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synapt...
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| مؤلفون آخرون: | , , , , , , , |
| منشور في: |
2019
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| _version_ | 1864513513991438336 |
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| author | Adrián Martín‐Segura (18615133) |
| author2 | Tariq Ahmed (5768081) Álvaro Casadomé‐Perales (18615136) Irene Palomares‐Perez (18615139) Ernest Palomer (349259) Axelle Kerstens (6183554) Sebastian Munck (355816) Detlef Balschun (8096618) Carlos G. Dotti (6872990) |
| author2_role | author author author author author author author author |
| author_facet | Adrián Martín‐Segura (18615133) Tariq Ahmed (5768081) Álvaro Casadomé‐Perales (18615136) Irene Palomares‐Perez (18615139) Ernest Palomer (349259) Axelle Kerstens (6183554) Sebastian Munck (355816) Detlef Balschun (8096618) Carlos G. Dotti (6872990) |
| author_role | author |
| dc.creator.none.fl_str_mv | Adrián Martín‐Segura (18615133) Tariq Ahmed (5768081) Álvaro Casadomé‐Perales (18615136) Irene Palomares‐Perez (18615139) Ernest Palomer (349259) Axelle Kerstens (6183554) Sebastian Munck (355816) Detlef Balschun (8096618) Carlos G. Dotti (6872990) |
| dc.date.none.fl_str_mv | 2019-03-18T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1111/acel.12932 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Age_associated_cholesterol_reduction_triggers_brain_insulin_resistance_by_facilitating_ligand_independent_receptor_activation_and_pathway_desensitization/25904428 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Neurosciences aging cholesterol insulin signaling |
| dc.title.none.fl_str_mv | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synaptic fraction of hippocampal neurons during aging leads to a decrease in synaptic plasticity evoked by glutamate receptor activation and also by receptor tyrosine kinase (RTK) signaling. As insulin and insulin growth factor activity are dependent on tyrosine kinase receptors, we investigated whether the constitutive loss of brain cholesterol is also involved in the decay of insulin function with age. Using long‐term depression (LTD) induced by application of insulin to hippocampal slices as a read‐out, we found that the decline in insulin function during aging could be monitored as a progressive impairment of insulin‐LTD. The application of a cholesterol inclusion complex, which donates cholesterol to the membrane and increases membrane cholesterol levels, rescued the insulin signaling deficit and insulin‐LTD. In contrast, extraction of cholesterol from hippocampal neurons of adult mice produced the opposite effect. Furthermore, in vivo inhibition of Cyp46A1, an enzyme involved in brain cholesterol loss with age, improved insulin signaling. Fluorescence resonance energy transfer (FRET) experiments pointed to a change in receptor conformation by reduced membrane cholesterol, favoring ligand‐independent autophosphorylation. Together, these results indicate that changes in membrane fluidity of brain cells during aging play a key role in the decay of synaptic plasticity and cognition that occurs at this late stage of life.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Aging Cell<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1111/acel.12932" target="_blank">https://dx.doi.org/10.1111/acel.12932</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_7da19c6ede61694fb27305e8b85e022e |
| identifier_str_mv | 10.1111/acel.12932 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25904428 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitizationAdrián Martín‐Segura (18615133)Tariq Ahmed (5768081)Álvaro Casadomé‐Perales (18615136)Irene Palomares‐Perez (18615139)Ernest Palomer (349259)Axelle Kerstens (6183554)Sebastian Munck (355816)Detlef Balschun (8096618)Carlos G. Dotti (6872990)Biomedical and clinical sciencesNeurosciencesagingcholesterolinsulin signaling<div><p>In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synaptic fraction of hippocampal neurons during aging leads to a decrease in synaptic plasticity evoked by glutamate receptor activation and also by receptor tyrosine kinase (RTK) signaling. As insulin and insulin growth factor activity are dependent on tyrosine kinase receptors, we investigated whether the constitutive loss of brain cholesterol is also involved in the decay of insulin function with age. Using long‐term depression (LTD) induced by application of insulin to hippocampal slices as a read‐out, we found that the decline in insulin function during aging could be monitored as a progressive impairment of insulin‐LTD. The application of a cholesterol inclusion complex, which donates cholesterol to the membrane and increases membrane cholesterol levels, rescued the insulin signaling deficit and insulin‐LTD. In contrast, extraction of cholesterol from hippocampal neurons of adult mice produced the opposite effect. Furthermore, in vivo inhibition of Cyp46A1, an enzyme involved in brain cholesterol loss with age, improved insulin signaling. Fluorescence resonance energy transfer (FRET) experiments pointed to a change in receptor conformation by reduced membrane cholesterol, favoring ligand‐independent autophosphorylation. Together, these results indicate that changes in membrane fluidity of brain cells during aging play a key role in the decay of synaptic plasticity and cognition that occurs at this late stage of life.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Aging Cell<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1111/acel.12932" target="_blank">https://dx.doi.org/10.1111/acel.12932</a></p>2019-03-18T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1111/acel.12932https://figshare.com/articles/journal_contribution/Age_associated_cholesterol_reduction_triggers_brain_insulin_resistance_by_facilitating_ligand_independent_receptor_activation_and_pathway_desensitization/25904428CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259044282019-03-18T03:00:00Z |
| spellingShingle | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization Adrián Martín‐Segura (18615133) Biomedical and clinical sciences Neurosciences aging cholesterol insulin signaling |
| status_str | publishedVersion |
| title | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| title_full | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| title_fullStr | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| title_full_unstemmed | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| title_short | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| title_sort | Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization |
| topic | Biomedical and clinical sciences Neurosciences aging cholesterol insulin signaling |