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

Abstract

The precise aetiology of Parkinsons 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 -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 the aSyn accumulation, glial cell activation and dopaminergic 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 behavioural impairment, OB atrophy, progression of aSyn pathology, neuroinflammation and neurodegeneration. Our findings also established a link between distinct astrocyte activation and dopaminergic (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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/677764v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@5a983eorg.highwire.dtl.DTLVardef@1c115ceorg.highwire.dtl.DTLVardef@17eb778org.highwire.dtl.DTLVardef@3f3fa4_HPS_FORMAT_FIGEXP M_FIG C_FIG