Systemic inflammation triggered by LPS does not exacerbate the toxicity of alpha-synuclein preformed fibrils in mice

Abstract

Aims: Parkinson’s disease is the second most common neurodegenerative disease worldwide, where many patients gradually develop Parkinson’s disease dementia. Preformed fibrils of alpha-synuclein (PFFs) can seed and transmit endogenous alpha-synuclein (aSyn) to phosphorylate and accumulate in LB-like structures, but severe effects can be observed long after injection. Our study aims to investigate whether systemic immune responses could accelerate the spread of aSyn pathology across the brain of C57BL/6 mice. Methods: PBS/PFFs (dosage: 3ug PFF) were stereotaxically injected into the medial forebrain bundle of wildtype 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 per se 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. However, no behavioral defects were observed. LPS failed to exacerbate the effect of aSyn PFFs when administered intraperitoneal. Conclusions: Our results agree with ours and other findings that aSyn PFFs injected into the brain mildly spreads across the brain, but with no apparent effect on behavior. However, non-sterilized systemic inflammation does not further speed up the spreading process.