Artemisinin Activates AMPK to Rescue Neuronal Cells and 3xTg Mice from Aβ1-42 Neurotoxicity.

INTRODUCTION Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a multifactorial etiology, including amyloid β1-42 (Aβ1-42) accumulation, oxidative stress, tau hyperphosphorylation, and neuroinflammation. Among these pathological processes, redox imbalance and inflammation are key drivers of neuronal injury and are closely linked to dysregulation of AMPK signaling. Artemisinin (ART), a clinically safe antimalarial sesquiterpene lactone, has emerged as a promising neuroprotective candidate due to its antioxidant and anti-inflammatory properties. However, its role in modulating AMP-activated protein kinase (AMPK)-dependent neuroprotection in AD remains to be fully elucidated. Given that AMPK is a master regulator of cellular energy homeostasis, oxidative stress mitigation, and neuronal survival, and that its progressive dysregulation heavily accelerates Alzheimer's disease pathology, this study aimed to determine whether artemisinin (ART) counteracts Aβ1-42-induced neurotoxicity through the targeted activation of AMPK signaling. This work provides critical mechanistic insights supporting the therapeutic repurposing of ART for AD intervention.

Methods

Therefore, Aβ1-42-insulted PC12 catecholaminergic, SH-SY5Y neuroblastoma, and primary neuronal cell cultures were used to assess the neuroprotective effects of ART. Compound C and shAMPK were used to confirm AMPK dependency. In vivo efficacy was assessed with 3xTg-AD mice.

Results

ART restored viability, reduced reactive oxygen species, stabilized mitochondrial function, and prevented apoptosis. AMPK was activated by ART in a dose- and time-dependent manner and was reversed by Compound C and shAMPK. In 3xTg-AD mice, ART elevated brain P-AMPK expression. Together, these results show that ART activates AMPK in relation to neuroprotection against Aβ-induced toxicity.

Discussion

These findings collectively demonstrate that ART confers robust neuroprotection primarily via AMPK activation, thereby restoring redox homeostasis, preserving mitochondrial structural integrity, and suppressing caspase-dependent apoptosis. The high consistency of these therapeutic effects across complementary in vitro and in vivo models highlights the indispensable role of the AMPK cascade.

Conclusion

Given its established clinical safety profile and high blood-brain barrier permeability, ART represents a compelling candidate for repurposing as a disease-modifying drug in AD.