Huang-Lian-Jie-Du decoction alleviates cognitive impairment in high-fat diet-induced obese mice via Trem2/Dap12/Syk pathway

Background

Cognitive impairment induced by a high-fat diet (HFD) is common, but its mechanism is largely unknown. Huang-Lian-Jie-Du (HLJD) decoction is a classical and powerful prescription in China. It consists of four medicinal plants and is widely used in traditional Chinese medicines (TCM). Studies have shown that HLJD decoction is effective in treating obesity, depression, and so on. However, the therapeutic mechanism of HLJD is still poorly understood.

Purpose

Our study aimed to explore whether inflammatory factors and Trem2/Dap12/Syk pathway are involved in this process and whether HLJD treatment can repair cognitive impairment in HFD-induced obesity.

Methods

To obtain the obese mice, male mice were treated with HFD (60 Kcal% fat) for 16 weeks. After an additional eight weeks, HLJD decoction was administered orally at doses of 4 and 8 g/kg daily for eight weeks. The mice were then subjected to four behavior tests. Aβ42, total Tau, inflammatory-related, and microglial dysregulation-related markers expression were measured. Molecular docking analysis was also conducted to predict the interaction of the chemical constituents of HLJD with human TREM2, DAP12, and SYK. HLJD at doses of 12.5, 25, and 50 µg/mL or limonin at concentrations of 12.5, 25, and 50 µM were used to treat BV2 cells for 24 h. CCK8 assay and Trem2, Dap12, Syk, and p-Syk expression were measured.

Results

Our study revealed that cognitive impairment was evident in mice treated with HFD, indicating the impact of obesity on cognitive function. The expression of Aβ42 and total Tau in the hippocampus (HIP) was significantly higher in obese (HFD-V) mice compared to normal control (NC-V) mice. The Il6, Il1b, and Il10 mRNA expression levels were also markedly increased in the HIP of obese mice. Furthermore, Trem2, Dap12, p-Syk, and Iba1 expression were elevated in the HIP of obese mice. Importantly, HLJD treatment was found to repair cognitive impairment and lower the protein expression of Aβ42, Tau, Trem2, Dap12, p-Syk, and the expression of Il6, Il1b, and Il10 mRNA in HIP of HFD-V mice. The increased expression of Trem2, Dap12, p-Syk, and Iba1 in HIP after HFD consumption could be reduced after receiving HLJD decoction. The compound Limonin showed a well-predicted binding energy with TREM2, DAP12, and SYK. BV2 cells with HLJD or limonin detected the mRNA expressions of Trem2/Dap12. HLJD at 25 and 50 µg/mL decreased Trem2, Dap12, and p-Syk protein levels in BV2 cells.

Conclusion

These results reveal that HLJD treatment could alleviate cognitive impairment in HFD-induced obese mice by controlling the activation of the Trem2/Dap12 pathway and reducing Syk phosphorylation in HIP microglia. HLJD and limonin suppressed Trem2/Dap12/Syk signaling pathway in BV2 cells. HLJD therapy might represent a novel treatment for patients with cognitive impairment induced by obesity.