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 APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 Tg mice, and that microglial reactivity and hippocampal IGF-1 and TNF mRNA levels were significantly elevated in aged APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA and IGF-1 in the aged APPswe/PS1ΔE9 Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.
Highlights
Alzheimer’s disease (AD) is an age-associated progressive neurodegenerative disease and the most common cause of dementia
We recently showed that tumor necrosis factor (TNF) mRNA levels in the neocortex correlate to the age-dependent increase in Aβ plaque-load as well as aging, and that microglial production of TNF was functionally correlated to microglial uptake of Aβ (Babcock et al, 2015)
Our results show that a subset of microglia in the aging APPswe/PS1 E9 Tg mouse retain the capacity to express IGF1 mRNA, suggesting that the increased insulin-like growth factor-1 (IGF-1) mRNA levels in the aged APPswe/PS1 E9 Tg mice may be ascribed to microglia
Summary
Alzheimer’s disease (AD) is an age-associated progressive neurodegenerative disease and the most common cause of dementia. The first evidence of microglia being a source of IGF-1 in the adult CNS was the finding of a transient deafferentation-induced up-regulation of IGF-1 mRNA in the perforant pathway innervated parts of the dentate gyrus in young, adult rats which functionally was suggested to be involved in deafferentation-induced axonal sprouting (Guthrie et al, 1995). This up-regulation of IGF-1 mRNA was reported to be attenuated in aged rats (Woods et al, 1998)
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