This study investigates the mechanisms by which systemic inflammation, specifically lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα), causes chronic neuroinflammation and progressive neurodegeneration in adult mice. The researchers administered a single dose of LPS or TNFα to wild-type and TNFα receptor-deficient mice to examine the transfer of peripheral inflammation to the brain and its neurodegenerative consequences. Key findings include: 1. **Chronic Neuroinflammation**: Systemic LPS administration led to rapid increases in brain TNFα levels that persisted for up to 10 months, while peripheral TNFα levels subsided within 9 hours for serum and 1 week for liver. This chronic inflammation activated microglia and increased the expression of pro-inflammatory factors such as TNFα, MCP-1, IL-1β, and NF-κB p65 in the brain. 2. **Neurodegeneration**: LPS treatment resulted in a delayed and progressive loss of dopaminergic neurons in the substantia nigra (SN), with a 23% loss at 7 months and a 47% loss at 10 months. This loss was more pronounced in the SN compared to other brain regions, likely due to the higher density of microglia in the SN. 3. **Role of TNFα**: TNFα was crucial for the transfer of peripheral inflammation to the brain and the subsequent neuroinflammation. Mice lacking TNFα receptors did not show elevated brain TNFα levels or microglial activation in response to systemic LPS or TNFα. 4. **Mechanisms of Neurodegeneration**: The study suggests that the initial entry of pro-inflammatory factors into the brain activates microglia, leading to the production of additional inflammatory factors and neuronal damage. This process creates a self-propelling cycle of neuroinflammation and neurodegeneration. These findings provide valuable insights into the potential pathogenesis and self-propelling nature of Parkinson's disease, highlighting the importance of understanding the mechanisms by which peripheral inflammation can lead to chronic neuroinflammation and progressive neurodegeneration.This study investigates the mechanisms by which systemic inflammation, specifically lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα), causes chronic neuroinflammation and progressive neurodegeneration in adult mice. The researchers administered a single dose of LPS or TNFα to wild-type and TNFα receptor-deficient mice to examine the transfer of peripheral inflammation to the brain and its neurodegenerative consequences. Key findings include: 1. **Chronic Neuroinflammation**: Systemic LPS administration led to rapid increases in brain TNFα levels that persisted for up to 10 months, while peripheral TNFα levels subsided within 9 hours for serum and 1 week for liver. This chronic inflammation activated microglia and increased the expression of pro-inflammatory factors such as TNFα, MCP-1, IL-1β, and NF-κB p65 in the brain. 2. **Neurodegeneration**: LPS treatment resulted in a delayed and progressive loss of dopaminergic neurons in the substantia nigra (SN), with a 23% loss at 7 months and a 47% loss at 10 months. This loss was more pronounced in the SN compared to other brain regions, likely due to the higher density of microglia in the SN. 3. **Role of TNFα**: TNFα was crucial for the transfer of peripheral inflammation to the brain and the subsequent neuroinflammation. Mice lacking TNFα receptors did not show elevated brain TNFα levels or microglial activation in response to systemic LPS or TNFα. 4. **Mechanisms of Neurodegeneration**: The study suggests that the initial entry of pro-inflammatory factors into the brain activates microglia, leading to the production of additional inflammatory factors and neuronal damage. This process creates a self-propelling cycle of neuroinflammation and neurodegeneration. These findings provide valuable insights into the potential pathogenesis and self-propelling nature of Parkinson's disease, highlighting the importance of understanding the mechanisms by which peripheral inflammation can lead to chronic neuroinflammation and progressive neurodegeneration.