IL‐1β/IL‐1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha‐Synuclein pathology in the olfactory bulb, substantia nigra and striatum

Abstract

Olfactory dysfunction is one of the early symptoms seen in Parkinson’s disease (PD). However, the mechanisms underlying olfactory pathology that impacts PD disease progression and post‐mortem appearance of alpha‐Synuclein (α‐Syn) inclusions in and beyond olfactory bulb in PD remain unclear. It has been suggested that environmental toxins inhaled through the nose can induce inflammation in the olfactory bulb (OB), where Lewy body (LB) is the first to be found, and then, spread to related brain regions. We hypothesize that OB inflammation triggers local α‐Syn pathology and promotes its spreading to cause PD. In this study, we evaluated this hypothesis by intranasal infusion of lipopolysaccharides (LPS) to induce OB inflammation in mice and examined cytokines expression and PD‐like pathology. We found intranasal LPS‐induced microglia activation, inflammatory cytokine expression and α‐Syn overexpression and aggregation in the OB via interleukin‐1β (IL‐1β)/IL‐1 receptor type I (IL‐1R1) dependent signaling. In addition, an aberrant form of α‐Syn, the phosphorylated serine 129 α‐Syn (pS129 α‐Syn), was found in the OB, substantia nigra (SN) and striatum 6 weeks after the LPS treatment. Moreover, 6 weeks after the LPS treatment, mice showed reduced SN tyrosine hydroxylase, decreased striatal dopaminergic metabolites and PD‐like behaviors. These changes were blunted in IL‐1R1 deficient mice. Further studies found the LPS treatment inhibited IL‐1R1‐dependent autophagy in the OB. These results suggest that IL‐1β/IL‐1R1 signaling in OB play a vital role in the induction and propagation of aberrant α‐Syn, which may ultimately trigger PD pathology.

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis

“…Studies herein where initiated because we had observed regionally specific anomalous PSER129 signal in untreated healthy wildtype mice. Interestingly others have observed this mitral cell staining phenomenon but not realized the significance 27 . We demonstrated that the anomalous PSER129 signal was likely an endogenous PSER129 population sensitive to PK digestion that occurred in the mitral cells of healthy mammals.…”

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

“…In addition, activated microglia have been associated with reduced autophagy, further contributing to a-syn aggregation. The deletion of IL-1R1 inhibited the transmission of a-syn and TH-positive cell loss (70). NLRP3 activation promotes the secretion of the inflammatory cytokine interleukin-1b/18 (IL-1b/18) and induces pyroptosis, a type of cell death that possesses the potential for inflammation, to rupture microglia to further release IL-1b (71).…”

Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

“…A recent study using intranasal infusion of endotoxin-lipopolysaccharide (LPS) to induce olfactory bulb (OB) inflammation in mice found that LPS triggered microglial activation, inflammatory cytokine expression, and phosphorylated αSyn accumulation in the OB and SN through IL-1β/IL-1 receptor 1-dependent signaling. 100 This finding suggests that inflammation, particularly IL-1, plays a role in mediating the initiation and propagation of αSyn pathology from the OB. 100 In relation to systemic inflammation, La Vitola et al 101 developed a PD mouse model through systemic administration of LPS followed by intracerebroventricular injection of an αSyn oligo-mer as well as an αSyn-overexpression transgenic mouse administered LPS.…”

“…100 This finding suggests that inflammation, particularly IL-1, plays a role in mediating the initiation and propagation of αSyn pathology from the OB. 100 In relation to systemic inflammation, La Vitola et al 101 developed a PD mouse model through systemic administration of LPS followed by intracerebroventricular injection of an αSyn oligo-mer as well as an αSyn-overexpression transgenic mouse administered LPS. The authors demonstrated that peripherally induced neuroinflammation influences the action of αSyn oligomers to potentiate a detrimental effect.…”