Emerging clinical studies suggest periodontitis is positively involved in cognitive decline in Alzheimer's disease (AD). In addition, periodontitis is also known related to osteoporosis with aging. We have found that chronic systemic exposure to Lipopolysaccharide from Porphyromonas gingivalis (PgLPS) could induce AD-like phenotype in middle-aged mice in previous research. However, the evidence and mechanism bridging bone loss and memory decline during periodontitis is still poor. The present study aimed to explore bone loss and hippocampus-dependent memory decline in middle-aged mice after chronic systemic exposure of PgLPS. Significant decrease of bone volume/tissue volume ratios as well as trabecular numbers, and significant increase of structure model indexes in the proximal tibia were determined in middle-aged mice at week 3 after chronic systemic exposure to PgLPS compared to control group. Moreover, significant memory decline and significant upregulated expression of IL-17 and IL-6 in microglia were detected at week 3 after systemic exposure to PgLPS. These findings provide the evidence that bone loss was parallel to hippocampus-dependent memory decline in middle-aged mice during chronic systemic exposure to PgLPS.