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bioRxiv · 10.1101/2021.08.12.456055

Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells

Smit, T.·Ormel, P. R.·Sluijs, J. A.·Hulshof, L. A.·Middeldorp, J.·de Witte, L. D.·Hol, E. M.·Donega, V.
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Abstract

Dysregulation of microglial function contributes to Alzheimers disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimers microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with A{beta} clearance. A{beta} oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to A{beta} oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNF. In contrast, the A{beta}1-42 oligomers did not induce an inflammatory profile or a classical HAM or DAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the A{beta}1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that A{beta}1-42 oligomers may trigger a protective response both in vitro and in vivo.

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Smit, T., Ormel, P. R., Sluijs, J. A., Hulshof, L. A., Middeldorp, J., de Witte, L. D., Hol, E. M., Donega, V.. 2021-08-13. Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells. https://doi.org/10.1101/2021.08.12.456055

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