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Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes

OBJECTIVE: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neu...

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Autores principales: Logan, Sreemathi, Pharaoh, Gavin A., Marlin, M. Caleb, Masser, Dustin R., Matsuzaki, Satoshi, Wronowski, Benjamin, Yeganeh, Alexander, Parks, Eileen E., Premkumar, Pavithra, Farley, Julie A., Owen, Daniel B., Humphries, Kenneth M., Kinter, Michael, Freeman, Willard M., Szweda, Luke I., Van Remmen, Holly, Sonntag, William E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870102/
https://www.ncbi.nlm.nih.gov/pubmed/29398615
http://dx.doi.org/10.1016/j.molmet.2018.01.013
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author Logan, Sreemathi
Pharaoh, Gavin A.
Marlin, M. Caleb
Masser, Dustin R.
Matsuzaki, Satoshi
Wronowski, Benjamin
Yeganeh, Alexander
Parks, Eileen E.
Premkumar, Pavithra
Farley, Julie A.
Owen, Daniel B.
Humphries, Kenneth M.
Kinter, Michael
Freeman, Willard M.
Szweda, Luke I.
Van Remmen, Holly
Sonntag, William E.
author_facet Logan, Sreemathi
Pharaoh, Gavin A.
Marlin, M. Caleb
Masser, Dustin R.
Matsuzaki, Satoshi
Wronowski, Benjamin
Yeganeh, Alexander
Parks, Eileen E.
Premkumar, Pavithra
Farley, Julie A.
Owen, Daniel B.
Humphries, Kenneth M.
Kinter, Michael
Freeman, Willard M.
Szweda, Luke I.
Van Remmen, Holly
Sonntag, William E.
author_sort Logan, Sreemathi
collection PubMed
description OBJECTIVE: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. METHODS: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-Cre(TAM)/igfr(f/f)). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfr(f/f) mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. RESULTS: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30–50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H(2)O(2)-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. CONCLUSIONS: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies.
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spelling pubmed-58701022018-03-28 Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes Logan, Sreemathi Pharaoh, Gavin A. Marlin, M. Caleb Masser, Dustin R. Matsuzaki, Satoshi Wronowski, Benjamin Yeganeh, Alexander Parks, Eileen E. Premkumar, Pavithra Farley, Julie A. Owen, Daniel B. Humphries, Kenneth M. Kinter, Michael Freeman, Willard M. Szweda, Luke I. Van Remmen, Holly Sonntag, William E. Mol Metab Original Article OBJECTIVE: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. METHODS: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-Cre(TAM)/igfr(f/f)). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfr(f/f) mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. RESULTS: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30–50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H(2)O(2)-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. CONCLUSIONS: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies. Elsevier 2018-02-02 /pmc/articles/PMC5870102/ /pubmed/29398615 http://dx.doi.org/10.1016/j.molmet.2018.01.013 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Logan, Sreemathi
Pharaoh, Gavin A.
Marlin, M. Caleb
Masser, Dustin R.
Matsuzaki, Satoshi
Wronowski, Benjamin
Yeganeh, Alexander
Parks, Eileen E.
Premkumar, Pavithra
Farley, Julie A.
Owen, Daniel B.
Humphries, Kenneth M.
Kinter, Michael
Freeman, Willard M.
Szweda, Luke I.
Van Remmen, Holly
Sonntag, William E.
Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title_full Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title_fullStr Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title_full_unstemmed Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title_short Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
title_sort insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870102/
https://www.ncbi.nlm.nih.gov/pubmed/29398615
http://dx.doi.org/10.1016/j.molmet.2018.01.013
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