Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis

Lee, Jia Y., Lee, John D., Phipps, Simon, Noakes, Peter G. and Woodruff, Trent M. (2015) Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation, 12 1: . doi:10.1186/s12974-015-0310-z

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Author Lee, Jia Y.
Lee, John D.
Phipps, Simon
Noakes, Peter G.
Woodruff, Trent M.
Title Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Journal name Journal of Neuroinflammation   Check publisher's open access policy
ISSN 1742-2094
Publication date 2015-05-13
Year available 2015
Sub-type Article (original research)
DOI 10.1186/s12974-015-0310-z
Open Access Status DOI
Volume 12
Issue 1
Total pages 8
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background
Amyotrophic lateral sclerosis (ALS) is a devastating late onset neurodegenerative disorder that is characterised by the progressive loss of upper and lower motor neurons. The mechanisms underlying ALS pathogenesis are unclear; however, there is emerging evidence the innate immune system, including components of the toll-like receptor (TLR) system, may drive disease progression. For example, toll-like receptor 4 (TLR4) antagonism in a spontaneous ‘wobbler mouse’ model of ALS increased motor function, associated with a decrease in microglial activation. This study therefore aimed to extend from these findings and determine the expression and function of TLR4 signalling in hSOD1G93A mice, the most widely established preclinical model of ALS.

Findings
TLR4 and one of its major endogenous ligands, high-mobility group box 1 (HMGB1), were increased during disease progression in hSOD1G93A mice, with TLR4 and HMGB1 expressed by activated microglia and astrocytes. hSOD1G93A mice lacking TLR4 showed transient improvements in hind-limb grip strength and significantly extended survival when compared to TLR4-sufficient hSOD1G93A mice.

Conclusion
These results suggest that enhanced glial TLR4 signalling during disease progression contributes to end-stage ALS pathology in hSOD1G93A mice.
Keyword HMGB1
Motor neuron disease
Neuro inflammation
TLR4
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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