Intranasal Rotenone Induces Alpha-Synuclein Accumulation, Neuroinflammation and Dopaminergic Neurodegeneration in Middle-Aged Mice.

Accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Previous studies suggest that α-syn pathology may originate from the olfactory bulb (OB) or gut in response to an unknown pathogen and later progress to the different brain regions. Aging is viewed as the utmost threat to PD development. Therefore, studies depicting the role of age in α-syn accumulation and its progression in PD are important. In the present study, we gave intranasal rotenone microemulsion for 6 weeks in 12-month-old female BALB/c mice and found olfactory dysfunction after 4 and 6 weeks of rotenone administration. Interestingly, motor impairment was observed only after 6 weeks. The animals were sacrificed after 6 weeks to perform western blotting and immunohistochemical studies to detect α-syn pathology, neuroinflammation and neurodegeneration. We found α-syn accumulation in OB, striatum, substantia nigra (SN) and cortex. Importantly, we found significant glial cell activation and neurodegeneration in all the analysed regions which were absent in our previous published studies with 3 months old mice even after they were exposed to rotenone for 9 weeks indicating age is a crucial factor for α-syn induced neuroinflammation and neurodegeneration. We also observed increased iron accumulation in SN of rotenone-exposed aged mice. Moreover, inflammaging was observed in OB and striatum of 12-month-old BALB/c mice as compared to 3-month-old BALB/c mice. In conclusion, there is a difference in sensitivity between adult and aged mice in the development and progression of α-syn pathology and subsequent neurodegeneration, for which inflammaging might be the crucial probable mechanism.