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

Sreemathi Logan, Gavin A. Pharaoh, M. Caleb Marlin, Dustin R. Masser, Satoshi Matsuzaki, Benjamin Wronowski, Alexander Yeganeh, Eileen E. Parks, Pavithra Premkumar, Julie A. Farley, Daniel B. Owen, Kenneth M. Humphries, Michael Kinter, Willard M. Freeman, Luke I. Szweda, Holly Van Remmen, William E. Sonntag

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 H2O2-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.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

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Somatomedin Receptors
Short-Term Memory
Amyloid
Astrocytes
Somatomedins
IGF Type 1 Receptor
Reactive Oxygen Species
Association Learning
Learning
Smegmamorpha
Gliosis
Organelle Biogenesis
Tamoxifen
Oxidation-Reduction
Alzheimer Disease
Antioxidants
Adenosine Triphosphate
Pathology

Keywords

  • Alzheimer's disease
  • Amyloid
  • IGF-1
  • Mitochondria
  • Primary astrocytes
  • ROS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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.

In: Molecular Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Logan, S, Pharaoh, GA, Marlin, MC, Masser, DR, Matsuzaki, S, Wronowski, B, Yeganeh, A, Parks, EE, Premkumar, P, Farley, JA, Owen, DB, Humphries, KM, Kinter, M, Freeman, WM, Szweda, LI, Van Remmen, H & Sonntag, WE 2018, 'Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes', Molecular Metabolism. https://doi.org/10.1016/j.molmet.2018.01.013
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. In: Molecular Metabolism. 2018.
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abstract = "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 H2O2-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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AU - Logan, Sreemathi

AU - Pharaoh, Gavin A.

AU - Marlin, M. Caleb

AU - Masser, Dustin R.

AU - Matsuzaki, Satoshi

AU - Wronowski, Benjamin

AU - Yeganeh, Alexander

AU - Parks, Eileen E.

AU - Premkumar, Pavithra

AU - Farley, Julie A.

AU - Owen, Daniel B.

AU - Humphries, Kenneth M.

AU - Kinter, Michael

AU - Freeman, Willard M.

AU - Szweda, Luke I.

AU - Van Remmen, Holly

AU - Sonntag, William E.

PY - 2018/1/1

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N2 - 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 H2O2-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.

AB - 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 H2O2-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.

KW - Alzheimer's disease

KW - Amyloid

KW - IGF-1

KW - Mitochondria

KW - Primary astrocytes

KW - ROS

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