Hancinone possesses potentials on increasing the ability of HMC3 cells to phagocytosis of Aβ1-42 via TREM2/Syk/PI3K/AKT/mTOR signaling pathway.

CONTEXT

The amyloid hypothesis is the most widely accepted explanation for Alzheimer's disease (AD). Failure of microglia Amyloid β-protein (1-42) (Aβ1-42) oligomer clearance and secondary neuroinflammation play a crucial role in the etiology in sporadic AD. Piper kadsura (Choisy) Ohwi (PkO), an herb of Chinese medicine, has anti-inflammation, antioxidation effects.

OBJECTIVE

To explore the impact of PkO and its active substances on Alzheimer's disease.

MATERIALS AND METHODS

We integrated drug prediction, network pharmacology and molecular docking techniques to systematically examine multi-scale mechanisms of PkO. Moreover, human Microglia Clone 3 (HMC3) were respectively incubated for 24 hours in the presence or absence of Syk inhibitor (SI, 100 nmol/L), β-amyloid (1-42) oligomer mixtures (called as Aβ oligomer hereafter, Aβ, 2.5 µM), or hancinone (HAN, 0.5 µM, 2.5 µM, 10 µM) to verify the target of the effect of PkO on Aβ oligomer-induced microglia.

RESULTS

Ultimately, we screened hancinone from PkO as a potential therapeutic agent for AD. Hancinone increased Triggering receptor expressed on myeloid cells 2 (TREM2), Syk, and p-Syk levels, up-regulated relative levels of p-PI3K, p-AKT, and mTOR, promoted the ability of HMC3 cells from the M1 phenotype to the M2 phenotype in Aβ or SI-stimulated HMC3 cells, and enhanced the phagocytic capacity of HMC3 cells to Aβ.

DISCUSSION AND CONCLUSIONS

Hancinone could regulate the phenotype of HMC3 cells and promote cell phagocytosis of Aβ by modulating the TREM2/Syk/PI3K/AKT/mTOR signaling pathway. This systematic exploration indicates that hancinone has the therapeutic effect on AD.