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Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice

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 inve...

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Autores principales: Myhre, Christa Løth, Thygesen, Camilla, Villadsen, Birgitte, Vollerup, Jeanette, Ilkjær, Laura, Krohn, Katrine Tækker, Grebing, Manuela, Zhao, Shuainan, Khan, Asif Manzoor, Dissing-Olesen, Lasse, Jensen, Morten Skovgaard, Babcock, Alicia A., Finsen, Bente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682662/
https://www.ncbi.nlm.nih.gov/pubmed/31417357
http://dx.doi.org/10.3389/fncel.2019.00308
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author Myhre, Christa Løth
Thygesen, Camilla
Villadsen, Birgitte
Vollerup, Jeanette
Ilkjær, Laura
Krohn, Katrine Tækker
Grebing, Manuela
Zhao, Shuainan
Khan, Asif Manzoor
Dissing-Olesen, Lasse
Jensen, Morten Skovgaard
Babcock, Alicia A.
Finsen, Bente
author_facet Myhre, Christa Løth
Thygesen, Camilla
Villadsen, Birgitte
Vollerup, Jeanette
Ilkjær, Laura
Krohn, Katrine Tækker
Grebing, Manuela
Zhao, Shuainan
Khan, Asif Manzoor
Dissing-Olesen, Lasse
Jensen, Morten Skovgaard
Babcock, Alicia A.
Finsen, Bente
author_sort Myhre, Christa Løth
collection PubMed
description 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 Aβ(42) 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.
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spelling pubmed-66826622019-08-15 Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice Myhre, Christa Løth Thygesen, Camilla Villadsen, Birgitte Vollerup, Jeanette Ilkjær, Laura Krohn, Katrine Tækker Grebing, Manuela Zhao, Shuainan Khan, Asif Manzoor Dissing-Olesen, Lasse Jensen, Morten Skovgaard Babcock, Alicia A. Finsen, Bente Front Cell Neurosci Neuroscience 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 Aβ(42) 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. Frontiers Media S.A. 2019-07-30 /pmc/articles/PMC6682662/ /pubmed/31417357 http://dx.doi.org/10.3389/fncel.2019.00308 Text en Copyright © 2019 Myhre, Thygesen, Villadsen, Vollerup, Ilkjær, Krohn, Grebing, Zhao, Khan, Dissing-Olesen, Jensen, Babcock and Finsen. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Neuroscience
Myhre, Christa Løth
Thygesen, Camilla
Villadsen, Birgitte
Vollerup, Jeanette
Ilkjær, Laura
Krohn, Katrine Tækker
Grebing, Manuela
Zhao, Shuainan
Khan, Asif Manzoor
Dissing-Olesen, Lasse
Jensen, Morten Skovgaard
Babcock, Alicia A.
Finsen, Bente
Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title_full Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title_fullStr Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title_full_unstemmed Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title_short Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP(swe)/PS1(ΔE9) Transgenic Mice
title_sort microglia express insulin-like growth factor-1 in the hippocampus of aged app(swe)/ps1(δe9) transgenic mice
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682662/
https://www.ncbi.nlm.nih.gov/pubmed/31417357
http://dx.doi.org/10.3389/fncel.2019.00308
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