Objective: To assess the efficacy of toll-like receptor 4(TLR4) agonists to ameliorate the functional and neuropathological phenotype of a transgenic mouse model of multiple system atrophy (MSA).

Background: TLR4 plays a role in the clearance of α-synuclein by activated microglia (Stefanova et al., 2011;Fellner et al., 2013) and may serve as a therapeutic target in α-synucleinopathies. While the classical TLR4 agonist lipopolysaccharide (LPS) triggers phagocytic activity and pro-inflammatory responses, monophosphoryl lipid A (MPLA) is a LPS derivative that exhibits unique immunomodulatory properties by triggering phagocytic activity without significant release of toxic cytokines/chemokines by macrophages.

Methods: Transgenic mice overexpressing α-synuclein in oligodendrocytes under the proteolipid protein promoter (MSA mice) were randomized in 4 groups and received weekly intraperitoneal injections of either MPLA, LPS or vehicle. After a 12-week treatment period motor behavior was assessed by the pole test. Brains and plasma samples were collected for further neuropathological and immunological analysis. Statistical analysis to compare groups was done by parametric or non-parametric one-way ANOVA as appropriate.

Results: We detected motor improvement in the MPLA groups as compared to MSA mice treated with vehicle only. Preliminary data point towards significant preservation of dopaminergic neurons in the substantia nigra pars compacta parallel to reduction of the density of α-synuclein inclusions in MPLA-treated MSA mice. While no changes in the cytokine/chemokine profile were detected in the brains of any of the treatment groups, chronic inflammatory response was found in the plasma only of LPS- but not of MPLA-treated MSA mice. Respectively, the survival of LPS-treated mice was significantly decreased, while no mortality was detected in the MPLA or vehicle groups during the 12 weeks observation period.

Conclusions: The detected motor improvement and nigral neuroprotection in MSA transgenic mice receiving MPLA is the first indication to support our hypothesis that TLR4 agonists may be beneficial in MSA transgenic mice. Importantly, MPLA in contrast to LPS showed non-toxic TLR4 agonist activity making it potentially interesting candidate for the therapy of MSA and related α-synucleinopathies. Acknowledgement: This study is supported by grants of the Austrian Science Fund (FWF) P25161, W1206-08, and F4414.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-tlr4-for-disease-modification-in-multiple-system-atrophy-experimental-evidence/