Therapeutic potential of 6BIO and DKK1-LRP6 inhibitor in Wnt/β-catenin pathway modulation for amyloid-β-induced Alzheimer's disease model

Abstract

Background

The Wnt/β-catenin signaling pathway plays a crucial role in central nervous system development, with emerging evidence linking its dysregulation to the progression of Alzheimer's disease (AD).

Objective

This study investigates the activation of Wnt signaling by targeting GSK3β and the DKK1/LRP6 interaction using a combination of 6BIO (6Bromoindirubin-3-oxime) and a novel gallocyanine derivative (8e) modulator.

Methods

We identified the interaction energy scores of both modulators with target proteins through an in-silico approach. Furthermore, the effects of 6BIO (10 µM) and 8e (20 µM) were assessed in SH-SY5Y cells treated with Aβ_1–42 (20 µM). The efficacy of these modulators was also evaluated in male Wistar rats through dose-ranging studies. An Alzheimer's disease model was established via intracerebroventricular injection of Aβ_1–42, followed by treatment with 6BIO (23.8 µg/kg/day, i.p.) and 8e (4.2 mg/kg/day, i.p.).

Results

Both modulators demonstrated favorable binding energy scores and dynamic simulation results against the targeted proteins. In Aβ_1–42-treated SHSY5Y cells, the combination of 6BIO and 8e significantly reduced reactive oxygen species production and apoptotic activity while modulating protein expression. In vivo study, rats treated with combination of 6BIO and 8e modulators exhibited improved neurobehavioral activity compared to AD model rats, along with altered expression of DKK1, β-catenin, p-tau, and pGSK3β. Additionally, decreased oxidative stress and apoptosis markers.

Conclusions

These findings suggest that the combined targeting of GSK3β and LRP6 represents a promising therapeutic strategy for AD. The combination of 6BIO and 8e shows potential as a novel modulator and warrants further investigation in clinical trials to assess its therapeutic efficacy.