Autophagy activation by Terminalia chebula Retz. reduce Aβ generation by shifting APP processing toward non-amyloidogenic pathway in APPswe transgenic SH-SY5Y cells

Abstract

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor protein (APP) metabolism pathway to non-amyloidogenic ways and inducing autophagy play key roles in AD pathology. In published reports, there is no research on the APP metabolic process of Terminalia chebula Retz. (T. Chebula).

Purpose: The study aims to assess the effects of T. Chebula in AD transgenic SH-SY5Y cells to determine its underlying mechanisms on reducing Aβ level by regulating APP metabolic process.

Methods: The effects of T. Chebula water extract (TWE) on APPswe transgenic SH-SY5Y cells were analyzed by cell viability. ELISA used to quantify extracellular Aβ_1-40 and Aβ_1-42 generations. Western blot and RT-PCR assays were chosen to detect the expression of proteins and genes. The acridine orange (AO) stain was used to label autophagic-vesicles.

Results: Treatment with TWE significantly suppressed the Aβ_1-40 and Aβ_1-42 generations of APPswe transgenic cells. TWE inhibited amyloidogenic pathway by reducing BACE1 expression, and promote non-amyloidogenic pathway by inducing ADAM10 level of APP metabolism. Additionally, TWE induced autophagy in APPswe transgenic cells involved in APP metabolism to shift the balance to non-amyloidogenic pathway.

Conclusion: In summary, our finding first time expounded that TWE can inhibit the generation of Aβ_1-40 and Aβ_1-42 in APPswe transgenic SH-SY5Y cells, which were regulated APP metabolism tends to non-amyloid metabolism pathway and mediated by autophagy. The results presented a novel finding for AD treatment of traditional natural medicines.

Keywords: ADAM10; Autophagy; Aβ; BACE1; Non-amyloidogenic pathway; Terminalia chebula Retz..