Systemic lipopolysaccharide (LPS) exposure in adult mice leads to chronic neuroinflammation and progressive neurodegeneration, primarily through the activation of microglia and the release of pro-inflammatory factors such as TNFα. The study demonstrates that a single systemic LPS injection results in a rapid and sustained increase in brain TNFα levels, which remains elevated for up to 10 months, while peripheral TNFα levels decline rapidly. This persistent brain TNFα production is associated with microglial activation and the progressive loss of dopaminergic neurons in the substantia nigra (SN), similar to Parkinson's disease (PD). The findings suggest that peripheral inflammation can transfer to the brain via TNFα, leading to chronic neuroinflammation and neurodegeneration. The study also shows that TNFα receptors are essential for this process, as mice lacking these receptors do not exhibit brain inflammation or neurodegeneration following systemic LPS or TNFα administration. The results highlight the role of TNFα in mediating the transfer of peripheral inflammation to the brain and the subsequent neurotoxic effects on dopaminergic neurons. The study provides insights into the mechanisms underlying neurodegenerative diseases, emphasizing the importance of neuroinflammation in their progression.Systemic lipopolysaccharide (LPS) exposure in adult mice leads to chronic neuroinflammation and progressive neurodegeneration, primarily through the activation of microglia and the release of pro-inflammatory factors such as TNFα. The study demonstrates that a single systemic LPS injection results in a rapid and sustained increase in brain TNFα levels, which remains elevated for up to 10 months, while peripheral TNFα levels decline rapidly. This persistent brain TNFα production is associated with microglial activation and the progressive loss of dopaminergic neurons in the substantia nigra (SN), similar to Parkinson's disease (PD). The findings suggest that peripheral inflammation can transfer to the brain via TNFα, leading to chronic neuroinflammation and neurodegeneration. The study also shows that TNFα receptors are essential for this process, as mice lacking these receptors do not exhibit brain inflammation or neurodegeneration following systemic LPS or TNFα administration. The results highlight the role of TNFα in mediating the transfer of peripheral inflammation to the brain and the subsequent neurotoxic effects on dopaminergic neurons. The study provides insights into the mechanisms underlying neurodegenerative diseases, emphasizing the importance of neuroinflammation in their progression.