Background Fine particulate matter (PM 2.5 )-induced neurological and mental diseases, such as cognitive impairment and stroke, tend to cause disability. In this study, we plan to find the appropriate biological indicators reflecting the early effects of PM 2.5 exposure and explore the toxicity of inhaling PM 2.5 along with its pathological mechanism on nervous system. Methods Male C57BL/6 mice were divided into 6 groups and exposed to concentrated PM 2.5 or filtered air for 2, 4 and 6 months, respectively. Their performances of ethology were tested by Morris water maze, elevated plus maze and buried food pellet test. Weight of whole brain and olfactory bulbs were recorded when the mice were sacrificed and the brain structure was observed by HE staining. ROS, SOD, IL-6, TNF-α, IL-1β, BDNF, β-hydroxybutyric, IgG, albumin, fibrinogen and plasminogen were tested. The mRNA expressions of the cortex were detected by RNA sequencing and real-time PCR, and the corresponding proteins were detected by Western blot. Results The spatial learning memory ability were impaired and the mice performed anxiously after PM 2.5 exposure. Relative brain weight decreased along with age and PM 2.5 inhaled exposure exceeded the process. But neuronal morphology, inflammatory cytokines, ROS, β-hydroxybutyric, BDNF, IgG and fibrinogen did not change. Intriguingly, SOD and albumin decreased, while plasminogen increased after PM 2.5 exposure. PI3K-AKT-FoxO1 pathway was activated after 6-month PM 2.5 exposure. Conclusion Albumin, A/G value and plasminogen are main serum indicators of early-stage (2 month) PM 2.5 exposure, and long-term (6 month) PM 2.5 exposure induced brain injury potentially through the activation of PI3K/AKT/FoxO1 pathway.