Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines

Spitzer P, Walter M, Göth C, Oberstein T, Linning P, Knölker HJ, Kornhuber J, Maler JM (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 11

Article Number: 1967

DOI: 10.3389/fimmu.2020.01967

Abstract

It has been previously shown that the amyloid precursor protein (APP) support the innate immune defense as an immune receptor. Amyloid β (Aβ) peptides seem to have properties of an antimicrobial peptide and can act as opsonines. In APP-deficient mouse models, a reduced secretion of cytokines has been observed. Still, it is unclear whether this can be attributed to the lack of APP or to the missing secretion of Aβ peptides. We inhibited the secretion of Aβ peptides in primary human monocyte derived macrophages with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl-ester (DAPT) or the β-secretase inhibitor GL-189. Alternatively, we knocked down APP by transfection with siRNA. We measured tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and interleukin (IL-10) by enzyme linked immunosorbent assay (ELISA) and evaluated the phagocytotic activity by flow cytometry. We observed reduced concentrations of TNFα and IL-6 in the media of APP^k/d macrophages and after inhibition of the β-, or γ-secretase, especially after additional immunological activation with lipopolysaccharide (LPS). Secretion of IL-10 was increased after pharmacological inhibition of APP processing when the macrophages were not immunologically activated but was decreased during LPS-induced inflammation in APP^k/d macrophages. No changes of the phagocytotic activity were observed. We conclude that macrophage APP and Aβ peptides support the initiation of an immune response and are involved in the regulation of TNFα, IL-6, and IL-10 secretion by human monocyte-derived macrophages.

Authors with CRIS profile

Involved external institutions

Technische Universität Dresden Germany (DE)

How to cite

APA:

Spitzer, P., Walter, M., Göth, C., Oberstein, T., Linning, P., Knölker, H.J.,... Maler, J.M. (2020). Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.01967

MLA:

Spitzer, Philipp, et al. "Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines." Frontiers in Immunology 11 (2020).

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