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.

Studies indicate that mutant α-synuclein (mαSyn) is involved in the pathogenesis of Parkinson’s disease (PD). The mαSyn expression leads to the loss of dopaminergic neurons in the substantia nigra (SN) and consequent motor dysfunctions. Additionally, studies found that PD was accompanied by extensive neuroinflammation of SN. However, it remains unclear as to whether microglia participate in the mαSyn pathology. This issue is addressed by using AAV-mα-Syn (A30P-A53T) to overexpress the human mαSyn in the SN in view of establishing the PD model. Subsequently, minocycline (Mino) was used to inhibit microglia activity, and an interleukin-1 receptor (IL-1R1) antagonist was used to hinder the IL-1R1 function. Finally, immunohistochemistry was used to analyze phosphorylated αSyn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. mαSyn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological αSyn 12 weeks after AAV injection. The data demonstrated that inhibiting microglial activation or hindering IL-1R1 reversed the persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system, and development of Lewy body pathology caused by human mαSyn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.