Fine particulate matter exposure and small cerebrovascular inflammation

摘要

Abstract Dementia is a major challenge to public health without effective therapy. Ambient fine particulate matter (PM) exposure significantly increases the risk for cognitive dysfunction and dementia with the mechanism(s) largely unknown. Animal studies have revealed that PM exposure significantly impairs cognition with decreased learning capability without clearly defined mechanisms. Small cerebrovascular diseases significantly contribute to vascular cognitive impairment and dementia. Preliminary studies showed that PM exposure resulted in significant small cerebrovascular inflammation with excessive reactive oxygen species (ROS) production in association with significant increases in serum TNF-α, IL-6, and IL-1β in male wildtype (WT) C57BL/6 mice. While PM exposure also induced significant cerebral vascular inflammation in female WT C57BL/6 mice, only IL-6 and IL-1β, not TNF-α, were significantly increased. Treatment of male WT mice with TNF-α, but not IL-6 or IL-1β, induced significant inflammation in small cerebral vasculature, and no inflammation was observed in small cerebral vessels in male TNF-α deficient mice with PM exposure. In contrast, treatment of female WT mice with IL-6 triggered a significant inflammation in cerebral vasculature, and no inflammation was present in cerebral vessels in female IL-6 deficient mice with PM exposure. Initial data also demonstrated that PM exposure significantly impaired the memory and learning capability in male mice that were effectively prevented with TNF-α deficiency (either with specific antibody treatment or TNF-α knockout). Thus, the present project was proposed to test the novel hypothesis that “PM exposure induces significant small cerebrovascular inflammation due to increased production of TNF-α in males and IL-6 in females, leading to cognitive dysfunction”. There are three specific aims: 1) to test the hypothesis that TNF-α mediates the effect of PM exposure on small cerebrovascular inflammation in males; 2) to test the hypothesis that IL-6 plays a critical role in PM exposure-induced small cerebrovascular inflammation in females; and 3) to investigate the mechanisms for sex differences in PM exposure-induced productions of TNF-α and IL-6. Aging WT C57BL/6 mice (both male and female) will be exposed to PM. ROS production and cerebral microvascular inflammation will be quantitatively evaluated at different time points after PM exposure. Brain MRI imaging will be performed to evaluate structural changes at baseline, 1 week (acute effect), and 2 months (chronic effect) after PM exposure. Mouse learning and memory capability will be longitudinally evaluated at baseline, 2, 4, and 8 weeks after PM exposure. Studies will also be conducted using male TNF-α deficient mice and female IL-6 receptor deficient mice, as well as macrophage depletion mouse model (both male and female) to define the mechanism(s). The data from the present project will provide important and novel information on the mechanisms for the development and progression of dementia in patients with PM exposure and help explore new approaches to preventing and treating dementia related to PM exposure.