Atractylenolide III Promotes Astrocyte Aβ Clearance by Up-regulating AQP4 to Improve Alzheimer’s Disease

Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz­heimer’s disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ 1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ 1-42 -induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ 1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ 1-42 -induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.