Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS)

Brain Behavior & Immunity - Health, vol. 33, pp. 100686

Abstract

CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1-359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1-359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1-359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1-359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1-359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.

Authors 11

1. А. Н. Трофимов

   Maastricht University

   Affiliation as printed

   Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, the Netherlands

2. Dmitrii Pavlov

   University of Calgary · Alberta Children's Hospital Research Institute · Hotchkiss Brain Institute

   Affiliation as printed

   Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada

3. Anand Goswami Aachen Institute for Neuropathology, University Clinic

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Neuropathology, University Clinic RWTH Aachen, Germany

4. Anna Gorlova

   Sechenov University

   Affiliation as printed

   Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Department of Normal Physiology, Sechenov First Moscow State Medical University, Russia

5. Kirill Chaprov

   Cardiff University

   Affiliation as printed

   Division of Pathophysiology (Biomedicine), School of Biosciences, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Cardiff University, UK

6. Aleksei Umriukhin

   Sechenov University

   Affiliation as printed

   Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Department of Normal Physiology, Sechenov First Moscow State Medical University, Russia

7. Allan V. Kalueff

   St Petersburg University

   Affiliation as printed

   Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia

8. Alexey V. Deykin

   Belgorod National Research University

   Affiliation as printed

   Joint Center for Genetic Technologies and Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia

9. Klaus‐Peter Lesch

   University of Würzburg · Maastricht University · Universitätsklinikum Würzburg

   Affiliation as printed

   Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, the Netherlands

   Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, University of Würzburg, Germany

10. Daniel C. Anthony corresponding

    University of Oxford

    Affiliation as printed

    Department of Pharmacology, University of Oxford, United Kingdom

11. Tatyana V. Strekalova corresponding

    University of Würzburg · Maastricht University · University of Oxford · Universitätsklinikum Würzburg

    Affiliation as printed

    Department of Pharmacology, University of Oxford, United Kingdom

    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, the Netherlands

    Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, University of Würzburg, Germany