The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T--Synuclein: Intranasal LPS Exposure on the A53T--Synuclein Transgenic Mouse Model of Parkinson's Disease

Aging and interactions between genetic and environmental factors are believed to be involved the chronic development of Parkinson's disease (PD). Among PD patients, abnormally aggregated alpha-synuclein is a major component of the Lewy body. Generally, the intranasal route is believed to be a gate way to the brain, and it assists environmental neurotoxins in entering the brain and is related to anosmia during early PD. The current study applies the chronic intranasal application of lipopolysaccharides (LPS) in 4-, 8-, 12- and 16-month-old A53T-alpha-synuclein (A53T-alpha-Syn) transgenic C57BL/6 mice at 2-day intervals for a 2-month period, for evaluating the behavioral, pathological, and biochemical changes and microglial activation in these animals. According to our results, after intranasal administration of LPS, A53T-alpha-Syn mice showed severe progressive anosmia, hypokinesia, selective dopaminergic (DAergic) neuronal losses, decreased striatal dopamine (DA) level, and enhanced alpha-synuclein accumulation within the substantia nigra (SN) in an age-dependent way. In addition, we found obvious NF-kB activation, Nurr1 inhibition, IL-1 beta, and TNF-alpha generation within the microglia of the SN. Conversely, the wild-type (WT) mice showed mild, whereas A53T-alpha-Syn mice had moderate PD-like changes among the old mice. This study demonstrated the synergistic effect of intranasal LPS and alpha-synuclein burden on PD development. Its underlying mechanism may be associated with Nurr1 inhibition within microglia and the amplification of CNS neuroinflammation. The mice with multiple factors, including aging, neuroinflammation, and alpha-synuclein mutation, have played a significant role in enhancing our understanding of how inflammation and alpha-synuclein mutation contribute to the neurodegeneration observed in PD.