A ‘brain-first’ mouse model of progressive alpha-synuclein pathology via intranasal rotenone administration

The precise etiology of Parkinson’s disease (PD) is still poorly understood, but it is thought to arise due to an intricate relationship between genes and the environment. Our study takes a unique approach to understanding the effect of environmental factors on the onset and progression of α-synuclein (aSyn) pathology, a key feature of PD, from the olfactory bulb (OB) to other brain regions. In the present study, we evaluated the time-dependent progression of PD-like pathology by administering rotenone intranasally for 5.5 months in C57BL/6 male mice. We performed olfactory and motor tests and examined aSyn accumulation, glial cell activation, and dopaminergic (DAergic) neurodegeneration after 3, 4, and 5.5 months of rotenone exposure by immunoblotting and immunofluorescence techniques. We observed a time-dependent progression of aSyn accumulation from the OB to other brain regions, including the mid-brain and cortex. Consistently, we observed a time-dependent behavioral impairment, OB atrophy, progression of aSyn pathology, neuroinflammation, and neurodegeneration. Our findings also established a link between distinct astrocyte activation and DAergic activity. In conclusion, this chronic and progressive mouse model mimics the brain-first type of progression of PD-like pathology in some PD patients, opening the possibility for testing potential disease-modifying interventions.