Artemether alleviates Aβ_1-42-induced neuronal cell damage via PGC-1α-mediated mitochondrial homeostasis in...

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia. Mitochondrial dysfunction is a key pathogenic event that drives neuronal damage and disease progression. Thus, protecting against mitochondrial damage in neuronal cells has become a critical therapeutic target for AD prevention and treatment. Our previous research has shown that artemether can protect PC12 cells from oxidative stress damage induced by Aβ and oxygen-glucose deprivation, but its underlying regulatory mechanisms remain elusive. Therefore, it is essential to elucidate the role and mechanism of artemether in Aβ-induced mitochondrial damage.

Evaluate the protective effects of artemether on Aβ-induced mitochondrial dysfunction and the underlying molecular mechanism in AD.

The HT-22 cell line and primary hippocampal neurons were employed in the present study owing to their greater physiological relevance to hippocampal neuronal injury. In order to evaluate the protective effects of artemether against mitochondrial damage in neuronal cells, we performed Cell Counting Kit-8 assays to assess cell viability and LDH release assays to measure cytotoxicity. Furthermore, we evaluated mitochondrial membrane potential, quantified ATP content, and detected ROS production in Aβ-induced neuronal cell damage. In addition, we used transmission electron microscopy to observe mitochondrial ultrastructural changes and performed immunofluorescence staining to analyze mitochondrial protein localization and morphology. In the AD mouse model, we conducted behavioral tests to assess cognitive function, while using H&E staining, immunohistochemistry, and TUNEL staining to evaluate artemether's effects on AD-related pathological hallmarks. Furthermore, Western blot analysis was performed to dissect the molecular mechanism underlying artemether's protective effect against Aβ-induced mitochondrial damage, focusing on the expression of key proteins in the PGC1/ERRα/TFAM signaling pathway.

Artemether protects against Aβ_1-42 induced mitochondrial damage in HT-22 cells and alleviates Aβ_1-42 injection induced memory deficits, mitochondrial dysfunction and neuroinflammation in the AD mice model. Mechanistically, artemether treatment upregulated the protein levels of PGC1, which contributes to mitochondrial homeostasis and further activation of the ERRα/TFAM signaling pathway. Moreover, Inhibition of PGC1α abrogates artemether's protective effects.

Our findings indicate that neuronal mitochondrial dysfunction serves as a central driver in AD pathogenesis, and activating the PGC1α/ERRα/TFAM axis through artemether offers an effective and feasible strategy for the prevention and treatment of AD.