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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00308

Microglia Express Insulin-like Growth Factor-1 in the Hippocampus of Aged APPswe/PS1dE9 Transgenic Mice

 Bente Finsen1, 2*,  Christa L. Myhre1,  Camilla Thygesen1, 2, 3,  Birgitte Villadsen1, 2,  Jeanette Vollerup1, 2, Laura Ilkjær1, Katrine T. Jensen1, 2, Manuela Grebing1,  Shuainan Zhao1,  Asif M. Khan1, Lasse Dissing-Olesen1,  Morten S. Jensen4 and  Alicia A. Babcock1
  • 1Department of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Denmark
  • 2Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Denmark
  • 3Department of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Denmark
  • 4Department of Biomedicine, Faculty of Health, Aarhus University, Denmark

Insulin-like growth factor-1 (IGF-1) is a pleiotrophic molecule with neurotrophic and immunomodulatory functions. Knowing the capacity of chronically activated microglia to produce IGF-1 may therefore show essential to promote beneficial microglial functions in Alzheimer’s disease. Here, we investigated the expression of IGF-1 mRNA along with the expression of tumor necrosis factor (TNF) mRNA, and the amyloid-β (Aβ) plaque load in the hippocampus of 3- to 24-month-old APPswe/PS1dE9 transgenic (Tg) and wild-type (WT) mice. As IGF-1, in particular, is implicated in neurogenesis we also monitored the proliferation of cells in the subgranular zone (sgz) of the dentate gyrus. We found that the Aβ plaque load reached a plateau in aged APPswe/PS1dE9 Tg mice, and that microglial reactivity and hippocampal IGF-1 and TNF mRNA levels were significantly elevated in aged APPswe/PS1dE9 Tg mice. IGF-1 mRNA was expressed in subsets of sgz cells, likely neuroblasts, and neurons in both genotypes, regardless of age, as well as in glial-like cells which double in situ hybridization showed to be IGF1 mRNA+/CD11b mRNA+ cells, i.e. IGF-1 mRNA expressing microglia. Quantification showed a two-fold increase in the number of microglia and IGF-1 mRNA+ microglia in the molecular layer of the dentate gyrus in aged APPswe/PS1dE9 Tg mice. Exposure of primary murine microglia and BV2 cells to Aβ42 did not affect IGF-1 mRNA expression. IGF-1 mRNA levels remained constant in WT mice with aging, unlike TNF mRNA levels which increased with aging. Finally, sgz cell proliferation decreased with age, regardless of genotype and the increased IGF-1 and TNF mRNA levels. In conclusion, our results suggest that the increased IGF-1 mRNA levels can be ascribed to a larger number of IGF-1 mRNA-expressing microglia in the aged APPswe/PS1dE9 Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA in the aged APPswe/PS1dE9 Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.

Keywords: Neuroinflammation, Tumor necrosis factor, Insulin-like growth factor, cerebral amyloidosis, Aging, Neurogenesis

Received: 23 Nov 2018; Accepted: 24 Jun 2019.

Edited by:

Raquel Ferreira, University of Beira Interior, Portugal

Reviewed by:

Daniela Tropea, Trinity College Dublin, Ireland
Aline Stephan, Université de Strasbourg, France  

Copyright: © 2019 Finsen, Myhre, Thygesen, Villadsen, Vollerup, Ilkjær, Jensen, Grebing, Zhao, Khan, Dissing-Olesen, Jensen and Babcock. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Bente Finsen, Department of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark,