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

Abstract

BackgroundAlpha-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.MethodsSix 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.ResultsChronic 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0195-7) contains supplementary material, which is available to authorized users.

Immune system responses in Parkinson's disease: Early and dynamic

“…This paradoxical observation suggests that the decrease in a‐syn uptake by the absence of TLR4 results in elevated extracellular a‐syn that can further promote a pro‐inflammatory response possibly through other receptors (such as CD11b or TLR2). On the other hand, treatment with a selective TLR4 agonist that promoted a‐syn clearance without inducing pro‐inflammatory activation, resulted in neuroprotection in vivo in the a‐syn MSA mouse model (Venezia et al., ). In parallel, as mentioned TLR2 has been associated with microglia activation induced by a specific a‐syn oligomeric confirmation associated with neuron‐released a‐syn (Kim et al., ).…”

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

“…As was seen in mouse macrophages, exposure to MLi2 blocked both Rab10 phosphorylation as well as -synuclein-induced upregulation of LRRK2 protein expression. Past studies suggested aggregated -synuclein may stimulate tolllike receptor 4 signaling pathways in myeloid cell activation (Fellner et al, 2013;Hughes et al, 2019;Venezia et al, 2017). However, application of a potent TLR4 inhibitor known to completely block LPS responses failed to block -synuclein fibril-induction of LRRK2 protein expression and Rab10 phosphorylation (Supplemental Figure 1).…”

Inflammatory Bowel Diseases and Parkinson’s Disease

“…Accumulation of ␣-syn is not necessarily specific to IBD but it is also related to GI inflammation and ␣-syn is a regulator of the immune system including [110,111]. A study from 2017 on pediatric patients, reported a positive correlation between the expression of ␣-syn in the enteric neurites of the upper GI tract and the degree of acute and chronic inflammation in the intestinal wall [112].…”