Investigation whether systemic immune responses triggered by LPS synergizes the neurotoxic effects of alpha-synuclein preformed fibrils in mice

Abstract

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. The disease is mainly characterized by defects in the nigrostriatal pathway, which cause motor deficits such as resting tremor and rigidity. As the disease progresses, the symptoms worsen and approximately 80% of PD patients experience memory deficits at late stage. Preformed fibrils of alpha-synuclein (PFFs) has in animals showed to seed and transmit endogenous alpha-synuclein (aSyn) to phosphorylate and accumulate in Lewy Body-like structures across the brain, however this transmission of pathology appears in a slow rate. This study therefore aims to investigate if systemic immune responses will accelerate the spread of aSyn pathology across the brain of C57BL/6J mice. Methods: PBS/PFFs (dosage: 3ug PFF) was stereotaxically injected into the medial forebrain bundle of mice, which later was challenged by one single intraperitoneal injection of PBS/LPS (dosage: 5 mg/kg). The behavior was examined 90 days after stereotaxical injection of PBS/PFF, and immunohistochemical techniques were used to detect aSyn pathology and other molecular effects. Results: aSyn PFFs showed a mild spread to various regions of the brain after injection into the medial forebrain bundle with a significant loss of tyrosine hydroxylase immunoreactive positive neurons in the substantia nigra ipsilateral to injection, but no behavioral defects were observed. LPS failed to exacerbate the effect of aSyn PFFs when administered intraperitoneal. Conclusions: In agreement with literature, our results demonstrated that aSyn PFFs injected into the brain mildly spreads across the brain, but with no apparent effect on behavior. More so, systemic inflammation did not acerbate the effects of aSyn PFF on a behavioral outcome. Further examination of the pathology will proceed to understand the role systemic immune responses has on the spread of aSyn pathology.