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

被引：128

作者：

Logan, Sreemathi ^{[1
]}

Pharaoh, Gavin A. ^{[2
,3
]}

Marlin, M. Caleb ^{[6
]}

Masser, Dustin R. ^{[1
,2
]}

Matsuzaki, Satoshi ^{[3
,4
]}

Wronowski, Benjamin ^{[1
,2
]}

Yeganeh, Alexander ^{[1
,5
]}

Parks, Eileen E. ^{[1
,5
]}

Premkumar, Pavithra ^{[3
]}

Farley, Julie A. ^{[1
]}

Owen, Daniel B. ^{[1
]}

Humphries, Kenneth M. ^{[3
,4
]}

Kinter, Michael ^{[3
]}

Freeman, Willard M. ^{[1
,2
,5
]}

Szweda, Luke I. ^{[3
,4
]}

Van Remmen, Holly ^{[2
,3
,5
]}

Sonntag, William E. ^{[1
,2
,5
]}

机构：

[1] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Norman, OK 73019 USA

[2] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Norman, OK 73019 USA

[3] Oklahoma Med Res Fdn, Aging & Metab Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA

[4] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Norman, OK 73019 USA

[5] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Neurosci, Norman, OK 73019 USA

[6] Univ Oklahoma, Hlth Sci Ctr, Grad Coll, Norman, OK 73019 USA

来源：

MOLECULAR METABOLISM | 2018年 / 9卷

关键词：

Primary astrocytes; IGF-1; Amyloid; Mitochondria; ROS; Alzheimer's disease; FACTOR-I IGF-1; NF-KAPPA-B; AMES DWARF; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; GLUCOSE-UTILIZATION; HYDROGEN-PEROXIDE; FREE-RADICALS; BRAIN; HORMONE;

D O I：

10.1016/j.molmet.2018.01.013

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective: A decline in mitochondria! 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 mitochondria! 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 mitochondria) 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 mitochondria! 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 A beta 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. (C) 2018 The Authors. Published by Elsevier GmbH.

引用

页码：141 / 155

页数：15

共 106 条

[41] Antioxidant enzymes, free-radical damage, and response to paraquat in liver and kidney of long-living growth hormone receptor/binding protein gene-disrupted mice [J].