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

## TL;DR

Hancinone, a compound from a Chinese herb, may help treat Alzheimer's by boosting microglia's ability to clear amyloid plaques through a specific signaling pathway.

## Contribution

Hancinone is identified as a novel compound that modulates microglial phagocytosis via the TREM2/Syk/PI3K/AKT/mTOR pathway in Alzheimer's disease.

## Key findings

- Hancinone increases TREM2, Syk, and p-Syk levels in HMC3 cells.
- Hancinone promotes phagocytosis of Aβ1-42 by modulating the TREM2/Syk/PI3K/AKT/mTOR pathway.
- Hancinone shifts HMC3 cells from M1 to M2 phenotype, enhancing Aβ clearance.

## Abstract

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.

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

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.

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.

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.