TY - JOUR
T1 - Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS)
AU - Trofimov, Alexander
AU - Pavlov, Dmitrii
AU - Goswami, Anand
AU - Gorlova, Anna
AU - Chaprov, Kirill
AU - Umriukhin, Aleksei
AU - Kalueff, Allan
AU - Deykin, Alexey
AU - Lesch, Klaus Peter
AU - Anthony, Daniel Clive
AU - Strekalova, Tatyana
N1 - Funding Information:
This study was supported by PhytoAPP EU framework , FGFU-2022-0013 , Priority Program-2030, the Gennady Kommissarov Young Scientists Foundation ( November-2019-RR ). The PhytoAPP project has received funding from the European Union's HORIZON-2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 101007642 . Transgenic animals were funded by grant for Laboratory of Genetic Technologies and genome editing for Biomedicine and Animal health (No. FZWG-2021-2016 ). Molecular studies were the Minobrnauki No.075-15-2021-1346.
Publisher Copyright:
© 2023
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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-1ß, 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.
AB - 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-1ß, 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.
KW - Amyotrophic lateral sclerosis (ALS)
KW - Cyclooxygenase-1 (COX-1)
KW - Cyclooxygenase-2 (COX-2)
KW - Emotionality
KW - Frontotemporal lobar degeneration (FTLD)
KW - Fused in sarcoma (FUS) protein
KW - Interleukin-1ß (IL-1ß)
KW - Lipopolysaccharide (LPS)
KW - Tumour necrosis factor (TNF)
U2 - 10.1016/j.bbih.2023.100686
DO - 10.1016/j.bbih.2023.100686
M3 - Article
SN - 2666-3546
VL - 33
JO - Brain, Behavior, & Immunity - Health
JF - Brain, Behavior, & Immunity - Health
IS - 1
M1 - 100686
ER -