Lipopolizakkarit (LPS) ve A53T-alfa-sinükleinin Sinerjik Etkisi Çalışması: Parkinson Hastalığının A53T-alfa-sinüklein Transgenik Fare Modeli Üzerine İntranazal LPS Maruziyeti

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Abstract Aging and the interaction between genetic and environmental factors are believed to be involved in chronic Parkinson's Disease (PD) progression. Abnormal aggregated α-synuclein is the main component of Lewy body in PD patients. The intranasal route is believed to be a gate way to the brain which facilitates entry of environmental neurotoxin into the brain and account for the smell loss in early PD. In this study, we chronically applied intranasal lipopolysaccharides (LPS) exposure on 4-month-old, 8-month-old, 12-month-old and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice every other day for 2 months to evaluate the behavioral, pathological, biochemical changes as well as microglial activation in these mice. We observed intranasal LPS exposed A53T-α-Syn mice displayed a robust progressive olfactory disorder, hypokinesia, selective loss of dopaminergic neurons, reduction in striatal dopamine (DA) content, and accelerated α-synuclein aggregation in the SN in an age-dependent way. Furthermore, we found obvious NF-кB activation, Nurr1 inhibition, IL-1β and TNF-α generation in microglia in the SN. By contrast, these PD-like changes were mild in WT and moderate in A53T-α-Syn mice in old-aged mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD progression. The potential mechanism was attributed to the inhibition of Nurr1 in microglial cells and the amplified neuroinflammation in the CNS. These multi-hit animals (aging, α-synuclein mutation and neuroinflammation) might help us to investigate the mechanisms through which mutant α-synuclein and inflammation work in concert to mediate PD neurodegeneration.

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