Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes

Christian Rungsted Andersson*, Jeppe Falsig, Jeffrey B. Stavenhagen, Søren Christensen, Fredrik Kartberg, Nina Rosenqvist, Bente Finsen, Jan Torleif Pedersen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Neurodegenerative diseases such as Alzheimer's disease are characterized by the progressive spreading and accumulation of hyper-phosphorylated tau protein in the brain. Anti-tau antibodies have been shown to reduce tau pathology in in vivo models and antibody-mediated clearance of tau exerted by microglia has been proposed as a contributing factor. By subjecting primary microglia cultured in vitro to anti-phospho-tau antibodies in complex with pathological tau, we show that microglia internalise and degrade tau in a manner that is dependent on FcγR interaction and functional lysosomes. It has recently been discussed if anti-tau antibody effector-functions are required for induction of tau clearance. Using antibodies with compromised FcγR binding and non-compromised control antibodies we show that antibody effector functions are required for induction of microglial clearance of tau. Understanding the inflammatory consequences of targeting microglia using therapeutic antibodies is important when developing these molecules for clinical use. Using RNA sequencing, we show that treatment with anti-tau antibodies increases transcription of mRNA encoding pro-inflammatory markers, but that the mRNA expression profile of antibody-treated cells differ from the profile of LPS activated microglia. We further demonstrate that microglia activation alone is not sufficient to induce significant tau clearance.

Original languageEnglish
Article number4658
JournalScientific Reports
Volume9
Issue number1
Number of pages12
ISSN2045-2322
DOIs
Publication statusPublished - 15. Mar 2019

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Fc Receptors
Microglia
RNA Sequence Analysis
tau Proteins
Messenger RNA
Neurodegenerative Diseases
Alzheimer Disease
Pathology

Cite this

Andersson, C. R., Falsig, J., Stavenhagen, J. B., Christensen, S., Kartberg, F., Rosenqvist, N., ... Pedersen, J. T. (2019). Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes. Scientific Reports, 9(1), [4658]. https://doi.org/10.1038/s41598-019-41105-4
Andersson, Christian Rungsted ; Falsig, Jeppe ; Stavenhagen, Jeffrey B. ; Christensen, Søren ; Kartberg, Fredrik ; Rosenqvist, Nina ; Finsen, Bente ; Pedersen, Jan Torleif. / Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "Neurodegenerative diseases such as Alzheimer's disease are characterized by the progressive spreading and accumulation of hyper-phosphorylated tau protein in the brain. Anti-tau antibodies have been shown to reduce tau pathology in in vivo models and antibody-mediated clearance of tau exerted by microglia has been proposed as a contributing factor. By subjecting primary microglia cultured in vitro to anti-phospho-tau antibodies in complex with pathological tau, we show that microglia internalise and degrade tau in a manner that is dependent on FcγR interaction and functional lysosomes. It has recently been discussed if anti-tau antibody effector-functions are required for induction of tau clearance. Using antibodies with compromised FcγR binding and non-compromised control antibodies we show that antibody effector functions are required for induction of microglial clearance of tau. Understanding the inflammatory consequences of targeting microglia using therapeutic antibodies is important when developing these molecules for clinical use. Using RNA sequencing, we show that treatment with anti-tau antibodies increases transcription of mRNA encoding pro-inflammatory markers, but that the mRNA expression profile of antibody-treated cells differ from the profile of LPS activated microglia. We further demonstrate that microglia activation alone is not sufficient to induce significant tau clearance.",
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Andersson, CR, Falsig, J, Stavenhagen, JB, Christensen, S, Kartberg, F, Rosenqvist, N, Finsen, B & Pedersen, JT 2019, 'Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes', Scientific Reports, vol. 9, no. 1, 4658. https://doi.org/10.1038/s41598-019-41105-4

Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes. / Andersson, Christian Rungsted; Falsig, Jeppe; Stavenhagen, Jeffrey B.; Christensen, Søren; Kartberg, Fredrik; Rosenqvist, Nina; Finsen, Bente; Pedersen, Jan Torleif.

In: Scientific Reports, Vol. 9, No. 1, 4658, 15.03.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Andersson, Christian Rungsted

AU - Falsig, Jeppe

AU - Stavenhagen, Jeffrey B.

AU - Christensen, Søren

AU - Kartberg, Fredrik

AU - Rosenqvist, Nina

AU - Finsen, Bente

AU - Pedersen, Jan Torleif

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AB - Neurodegenerative diseases such as Alzheimer's disease are characterized by the progressive spreading and accumulation of hyper-phosphorylated tau protein in the brain. Anti-tau antibodies have been shown to reduce tau pathology in in vivo models and antibody-mediated clearance of tau exerted by microglia has been proposed as a contributing factor. By subjecting primary microglia cultured in vitro to anti-phospho-tau antibodies in complex with pathological tau, we show that microglia internalise and degrade tau in a manner that is dependent on FcγR interaction and functional lysosomes. It has recently been discussed if anti-tau antibody effector-functions are required for induction of tau clearance. Using antibodies with compromised FcγR binding and non-compromised control antibodies we show that antibody effector functions are required for induction of microglial clearance of tau. Understanding the inflammatory consequences of targeting microglia using therapeutic antibodies is important when developing these molecules for clinical use. Using RNA sequencing, we show that treatment with anti-tau antibodies increases transcription of mRNA encoding pro-inflammatory markers, but that the mRNA expression profile of antibody-treated cells differ from the profile of LPS activated microglia. We further demonstrate that microglia activation alone is not sufficient to induce significant tau clearance.

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