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  Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion

Garcia-Agudo, L. F., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., et al. (2019). Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion. The FASEB Journal, 33(7), 8634-8647. doi:10.1096/fj.201900337R.

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 Creators:
Garcia-Agudo, Laura Fernandez1, Author           
Janova, Hana1, Author           
Sendler, Lea E.1, Author           
Arinrad, Sahab1, Author           
Steixner, Agnes A.1, Author           
Hassouna, Imam1, Author           
Balmuth, Evan1, Author           
Ronnenberg, Anja1, Author           
Schopf, Nadine1, Author           
van der Flier, Felicia J.1, Author           
Begemann, Martin1, Author           
Martens, Henrik, Author
Weber, Martin S., Author
Boretius, Susann, Author
Nave, Klaus-Armin2, Author           
Ehrenreich, Hannelore1, Author           
Affiliations:
1Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173651              
2Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173664              

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Free keywords: CSF1R inhibitor PLX5622; Catatonic signs; Executive function; Hurdle test; Phagocytosis
 Abstract: Reduced expression of 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation via colony-stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly 1) the comparison of 2 long-term PLX5622 applications (prevention and treatment) vs. 1 treatment alone, 2) the correlation of catatonic signs and executive dysfunction, 3) the phenotype of leftover microglia evading depletion, and 4) the role of intercellular interactions for efficient CSF1R inhibition. Based on our Cnp–/– mouse model and in vitro time-lapse imaging, we report the unexpected discovery that microglia surviving under PLX5622 display a highly inflammatory phenotype including aggressive premortal phagocytosis of oligodendrocyte precursor cells. Interestingly, ablating microglia in vitro requires mixed glial cultures, whereas cultured pure microglia withstand PLX5622 application. Importantly, 2 extended rounds of CSF1R inhibition are not superior to 1 treatment regarding any readout investigated (magnetic resonance imaging and magnetic resonance spectroscopy, behavior, immunohistochemistry). Catatonia-related executive dysfunction and brain atrophy of Cnp–/– mice fail to improve under PLX5622. To conclude, even though microglia depletion is temporarily beneficial and worth pursuing, complementary treatment strategies are needed for full and lasting recovery.—Fernandez Garcia-Agudo, L., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., Balmuth, E., Ronnenberg, A., Schopf, N., van der Flier, F. J., Begemann, M., Martens, H., Weber, M. S., Boretius, S., Nave, K.-A., Ehrenreich, H. Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion.

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Language(s): eng - English
 Dates: 2019-05-152019-07
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1096/fj.201900337R
 Degree: -

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Title: The FASEB Journal
  Other : FASEB J.
Source Genre: Journal
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Publ. Info: Bethesda, Md. : The Federation
Pages: - Volume / Issue: 33 (7) Sequence Number: - Start / End Page: 8634 - 8647 Identifier: ISSN: 0892-6638
CoNE: https://pure.mpg.de/cone/journals/resource/954927535970_1