Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Open accessAbstract
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 hSOD1(G93A) 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 hSOD1(G93A) mice, with TLR4 and HMGB1 expressed by activated microglia and astrocytes. hSOD1(G93A) mice lacking TLR4 showed transient improvements in hind-limb grip strength and significantly extended survival when compared to TLR4-sufficient hSOD1(G93A) mice. CONCLUSION: These results suggest that enhanced glial TLR4 signalling during disease progression contributes to end-stage ALS pathology in hSOD1(G93A) mice.
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TLR4 deficiency or antagonist treatment improved motor function in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [309]
The Results section reports improved hind-limb grip strength at select ages in hSOD1G93A mice lacking TLR4. The Introduction describes antagonist-related motor improvement in a different ALS model, the wobbler mouse; this paper does not establish that antagonist treatment improved motor function in hSOD1G93A mice. Page numbers are unavailable in our copy. (LLM, conf=0.91)
Experimental — accuracy not yet measuredTLR4 deficiency or antagonist treatment extended life expectancy in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [309]
The Results report that TLR4-deficient hSOD1G93A mice survived longer than TLR4-sufficient mice (median 184 versus 169 days). The Discussion proposes exploring TLR4 inhibitors as a future strategy; this paper does not report that antagonist treatment extended survival. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTLR4 deficiency or antagonist treatment decreased microglia activation in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [309]
The Abstract Background reports decreased microglial activation after TLR4 antagonism, but in wobbler mice, not hSOD1G93A mice. For hSOD1G93A mice, the Discussion reports improved survival and grip strength after TLR4 deletion and proposes a microglial mechanism; it does not report a measured decrease in microglial activation. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the hSOD1 G93A transgenic mouse model, TLR4 expression was upregulated in microglia and astrocytes.
“In the hSOD1 G93A transgenic mouse model, the expression of TLR4 was upregulated in microglia and astrocytes”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [309]
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References 21 · Cited by 89
Research works printed but not linked: 16
- [1]Bruijn LI Miller TM Cleveland DW Unraveling the mechanisms involved in motor neuron degeneration in ALS Annu Rev Neurosci. 2004 27 723 49 10.1146/annurev.neuro.27.070203.144244 15217349 · DOI
- [3]Evans MC Couch Y Sibson N Turner MR Inflammation and neurovascular changes in amyotrophic lateral sclerosis Mol Cell Neurosci. 2013 53 34 41 10.1016/j.mcn.2012.10.008 23110760 · DOI
- [4]McGeer PL McGeer EG Inflammatory processes in amyotrophic lateral sclerosis Muscle Nerve. 2002 26 459 70 10.1002/mus.10191 12362410 · DOI · Paper page
- [5]Mantovani S Gordon R Macmaw JK Pfluger CM Henderson RD Noakes PG Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood J Neuroimmunol. 2014 276 213 8 10.1016/j.jneuroim.2014.09.005 25262158 · DOI
- [6]Jou I Lee JH Park SY Yoon HJ Joe EH Park EJ Gangliosides trigger inflammatory responses via TLR4 in brain glia Am J Pathol. 2006 168 1619 30 10.2353/ajpath.2006.050924 16651628 PMC1606595 · DOI
- [7]Tang SC Arumugam TV Xu X Cheng A Mughal MR Jo DG Pivotal role for neuronal toll-like receptors in ischemic brain injury and functional deficits Proc Natl Acad Sci U S A. 2007 104 13798 803 10.1073/pnas.0702553104 17693552 PMC1959462 · DOI · Paper page
- [9]Elliott JL Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis Brain Res Mol Brain Res. 2001 95 172 8 10.1016/S0169-328X(01)00242-X 11687290 · DOI
- [10]Letiembre M Liu Y Walter S Hao W Pfander T Wrede A Screening of innate immune receptors in neurodegenerative diseases: a similar pattern Neurobiol Aging. 2009 30 759 68 10.1016/j.neurobiolaging.2007.08.018 17905482 · DOI · Paper page
- [12]Lee JD Kamaruzaman NA Fung JN Taylor SM Turner BJ Atkin JD Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis J Neuroinflammation. 2013 10 119 10.1186/1742-2094-10-119 24067070 PMC3850877 · DOI
- [13]Ludolph AC Bendotti C Blaugrund E Hengerer B Loffler JP Martin J Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC international workshop Amyotroph Lateral Scler. 2007 8 217 23 10.1080/17482960701292837 17653919 · DOI
- [15]Woodruff TM Lee JD Noakes PG Role for terminal complement activation in amyotrophic lateral sclerosis disease progression Proc Natl Acad Sci U S A. 2014 111 E3 4 10.1073/pnas.1321248111 24381160 PMC3890900 · DOI
- [16]Lee JD, Lee JY, Taylor SM, Noakes PG, Woodruff TM. Innate Immunity in ALS. In Amyotrophic Lateral Sclerosis. Edited by (Ed.) PMM: InTech; 2012
- [17]Yamamoto M Takeda K Current views of toll-like receptor signaling pathways Gastroenterol Res Pract. 2010 2010 240365 10.1155/2010/240365 21197425 PMC3010626 · DOI
- [18]Hua F Ma J Ha T Xia Y Kelley J Williams DL Activation of toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion J Neuroimmunol. 2007 190 101 11 10.1016/j.jneuroim.2007.08.014 17884182 PMC2453597 · DOI
- [19]Walter S Letiembre M Liu Y Heine H Penke B Hao W Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease Cell Physiol Biochem. 2007 20 947 56 10.1159/000110455 17982277 · DOI · Paper page
- [20]Woodruff TM Costantini KJ Crane JW Atkin JD Monk PN Taylor SM The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis J Immunol. 2008 181 8727 34 10.4049/jimmunol.181.12.8727 19050293 · DOI
- Authors
- Lee, J. Y., Lee, J. D., Phipps, S., Noakes, P. G., & Woodruff, T. M.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Woodruff, Trent M
- Venue
- Journal of Neuroinflammation
- Published
- 2015-05-13
- Volume
- 12
- Issue
- 1
- Pages
- 90-90
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4431460
- OpenAlex
- W2147758827
- Cited by
- 89
- References
- 21
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 6 · 2021: 12 · 2020: 8 · 2019: 3 · 2018: 11 · 2017: 10 · 2016: 6 · 2015: 2
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council (0000-0003-1382-911X)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- amyotrophic lateral sclerosis, TLR4, HMGB1, microglial activation, astrocytes, innate immunity, neuroinflammation, survival, grip strength, motor neuron disease
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Body Weight, Calcium-Binding Proteins, Choline O-Acetyltransferase, Disease Models, Animal, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hindlimb, Humans, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, RNA, Messenger, Spinal Cord, Superoxide Dismutase, Survival Analysis, HMGB1 Protein, Toll-Like Receptor 3, Mice, Muscle Strength
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