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

Alexander Trofimov; Dmitrii Pavlov; Anand Goswami; Anna Gorlova; Kirill Chaprov; Aleksei Umriukhin; Allan Kalueff; Alexey Deykin; Klaus-Peter Lesch; Daniel Clive Anthony; Tatyana Strekalova

doi:10.1016/j.bbih.2023.100686

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

Brain Behav Immun Health. 2023 Sep 15:33:100686. doi: 10.1016/j.bbih.2023.100686. eCollection 2023 Nov.

Authors

Alexander Trofimov¹, Dmitrii Pavlov², Anand Goswami³, Anna Gorlova⁴, Kirill Chaprov⁵, Aleksei Umriukhin⁴, Allan Kalueff⁶, Alexey Deykin⁷, Klaus-Peter Lesch^{1

8}, Daniel Clive Anthony⁹, Tatyana Strekalova^{1

8

9}

Affiliations

¹ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, the Netherlands.
² Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
³ Institute for Neuropathology, University Clinic RWTH Aachen, Germany.
⁴ Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Department of Normal Physiology, Sechenov First Moscow State Medical University, Russia.
⁵ Division of Pathophysiology (Biomedicine), School of Biosciences, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Cardiff University, UK.
⁶ Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
⁷ Joint Center for Genetic Technologies and Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia.
⁸ Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, University of Würzburg, Germany.
⁹ Department of Pharmacology, University of Oxford, United Kingdom.

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.

Keywords: Amyotrophic lateral sclerosis (ALS); Cyclooxygenase-1 (COX-1); Cyclooxygenase-2 (COX-2); Emotionality; Frontotemporal lobar degeneration (FTLD); Fused in sarcoma (FUS) protein; Interleukin-1β (IL-1β); Lipopolysaccharide (LPS); Tumour necrosis factor (TNF).