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

35 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)141-155
Number of pages15
JournalMolecular Metabolism
Volume9
DOIs
StatePublished - Mar 2018

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes'. Together they form a unique fingerprint.

  • Cite this

    Logan, S., Pharaoh, G. A., Marlin, M. C., Masser, D. R., Matsuzaki, S., Wronowski, B., Yeganeh, A., Parks, E. E., Premkumar, P., Farley, J. A., Owen, D. B., Humphries, K. M., Kinter, M., Freeman, W. M., Szweda, L. I., Van Remmen, H., & Sonntag, W. E. (2018). Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Molecular Metabolism, 9, 141-155. https://doi.org/10.1016/j.molmet.2018.01.013