Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APPswe/PS1ΔE9 Transgenic Mice

Christa Løth Myhre; Camilla Thygesen; Birgitte Villadsen; Jeanette Vollerup; Laura Ilkjær; Katrine Tækker Krohn; Manuela Grebing; Shuainan Zhao; Asif Manzoor Khan; Lasse Dissing-Olesen; Morten Skovgaard Jensen; Alicia A Babcock; Bente Finsen

doi:10.3389/fncel.2019.00308

Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP_swe/PS1_ΔE9 Transgenic Mice

Front Cell Neurosci. 2019 Jul 30:13:308. doi: 10.3389/fncel.2019.00308. eCollection 2019.

Authors

Christa Løth Myhre¹, Camilla Thygesen^{1

2

3}, Birgitte Villadsen^{1

2}, Jeanette Vollerup^{1

2}, Laura Ilkjær¹, Katrine Tækker Krohn^{1

2}, Manuela Grebing¹, Shuainan Zhao^{1

2}, Asif Manzoor Khan¹, Lasse Dissing-Olesen¹, Morten Skovgaard Jensen⁴, Alicia A Babcock¹, Bente Finsen^{1

2}

Affiliations

¹ Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
² Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³ Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
⁴ Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Abstract

Insulin-like growth factor-1 (IGF-1) is a pleiotropic 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 (AD). Here, we investigated the expression of IGF-1 mRNA and IGF-1 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 APP_swe/PS1_ΔE9 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 its maximum in aged 21- and 24-month-old APP_swe/PS1_ΔE9 Tg mice, and that microglial reactivity and hippocampal IGF-1 and TNF mRNA levels were significantly elevated in aged APP_swe/PS1_ΔE9 Tg mice. The sgz cell proliferation decreased with age, regardless of genotype and increased IGF-1/TNF mRNA levels. Interestingly, 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. By double in situ hybridization these were shown to be IGF1 mRNA⁺ CD11b mRNA⁺ cells, i.e., IGF-1 mRNA-expressing microglia. Quantification showed a 2-fold increase in the number of microglia and IGF-1 mRNA-expressing microglia in the molecular layer of the dentate gyrus in aged APP_swe/PS1_ΔE9 Tg mice. Double-immunofluorescence showed that IGF-1 was expressed in a subset of Aβ plaque-associated CD11b⁺ microglia and in several subsets of neurons. 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. 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 APP_swe/PS1_ΔE9 Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA and IGF-1 in the aged APP_swe/PS1_ΔE9 Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.

Keywords: aging; cerebral amyloidosis; insulin-like growth factor; neurogenesis; neuroinflammation; tumor necrosis factor.