Journal Article

Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal α-synucleinopathy

Refolo, Violetta, Polissidis, Alexia, Stefanis, Leonidas, Stefanova, Nadia, Wenning, Gregor K., Venezia, Serena

2017

Overview

Background Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innate immunity response. It was previously shown that TLR4 plays a role in the clearance of α-syn, suggesting that TLR4 up-regulation in microglia may be a natural mechanism to improve the clearance of α-syn. However, administration of TLR4 ligands could also lead to dangerous adverse effects associated with the induction of toxic inflammatory responses. Monophosphoryl lipid A (MPLA) is a TLR4 selective agonist and a potent inducer of phagocytosis which does not trigger strong toxic inflammatory responses as compared to lipopolysaccharide (LPS). We hypothesize that MPLA treatment will lead to increased clearance of α-syn inclusions in the brain of transgenic mice overexpressing α-syn in oligodendrocytes under the proteolipid protein promoter (PLP-α-syn mouse model of MSA), without triggering toxic cytokine release, thus leading to a general amelioration of the pathology. Methods Six month old PLP-α-syn mice were randomly allocated to four groups and received weekly intraperitoneal injections of MPLA (50 or 100 μg), LPS or vehicle. After a 12-week treatment period, motor behavior was assessed with the pole test. Brains and plasma samples were collected for neuropathological and immunological analysis. Results Chronic systemic MPLA treatment of PLP-α-syn mice led to increased uptake of α-syn by microglial cells, a significant motor improvement, rescue of nigral dopaminergic and striatal neurons and region-specific reduction of the density of oligodendroglial α-syn cytoplasmic inclusions in the absence of a marked systemic inflammatory response. Conclusion Our findings demonstrate beneficial effects of chronic MPLA treatment in transgenic PLP-α-syn mice. MPLA appears to be an attractive therapeutic candidate for disease modification trials in MSA and related α-synucleinopathies.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: alpha-Synuclein - metabolism / Alzheimer's disease / Animals / Atrophy / Biomedical and Life Sciences / Biomedicine / Brain / Chemokines / Cytotoxicity / Dementia disorders / Disease Models, Animal / Dopamine receptors / Female / Gene expression / Inclusion bodies / Inclusion pathology / Inflammation / Innate immunity / Laboratories / Lewy bodies / Lipid A / Lipid A - analogs & derivatives / Lipid A - metabolism / Lipids / Lipopolysaccharides / Male / Mice, Transgenic / Microglia / Microglial cells / Molecular Medicine / Monophosphoryl lipid A / Motor task performance / Movement disorders / Multiple System Atrophy - pathology / Neostriatum / Neurodegeneration / Neurodegenerative diseases / Neuroinflammation / Neurology / Neurons - metabolism / Neurosciences / Oligodendrocytes / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson's disease / Pathogens / Pathology / Phagocytosis / Proteins / Proteolipid protein / Research Article / Rodents / Side effects / Studies / Substantia nigra / Substantia Nigra - pathology / Synuclein / Toll-like receptor / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Transgenic animals / Transgenic mice / α-synuclein