Icaritin greatly attenuates -amyloid-induced toxicity in vivo

Aims: The accumulation and deposition of beta-amyloid (A beta) has always been considered a major pathological feature of Alzheimer's disease (AD). The latest and mainstream amyloid cascade hypothesis indicates that all the main pathological changes in AD are attributed to the accumulation of soluble A beta. However, the exploration of therapeutic drugs for A beta toxicity has progressed slowly. This study aims to investigate the protective effects of Icaritin on the A beta-induced Drosophila AD model and its possible mechanism.Methods: To identify the effects of Icaritin on AD, we constructed an excellent Drosophila AD model named A beta arc (arctic mutant A beta 42) Drosophila. Climbing ability, flight ability, and longevity were used to evaluate the effects of Icaritin on AD phenotypes. A beta arc was determined by immunostaining and ELISA. To identify the effects of Icaritin on oxidative stress, we performed the detection of ROS, hydrogen peroxide, MDA, SOD, catalase, GST, and Caspase-3. To identify the effects of Icaritin on energy metabolism, we performed the detection of ATP and lactate. Transcriptome analysis and qRT-PCR verifications were used to detect the genes directly involved in oxidative stress and energy metabolism. Mitochondrial structure and function were detected by an electron microscopy assay, a mitochondrial membrane potential assay, and a mitochondrial respiration assay.Results: We discovered that Icaritin almost completely rescues the climbing ability, flight ability, and longevity of A beta arc Drosophila. A beta arc was dramatically reduced by Icaritin treatment. We also found that Icaritin significantly reduces oxidative stress and greatly improves impaired energy metabolism. Importantly, transcriptome analysis and qRT-PCR verifications showed that many key genes, directly involved in oxidative stress and energy metabolism, are restored by Icaritin. Next, we found that Icaritin perfectly restores the integrity of mitochondrial structure and function damaged by A beta arc toxicity.Conclusion: This study suggested that Icaritin is a potential drug to deal with the toxicity of A beta arc, at least partially realized by restoring the mitochondria/oxidative stress/energy metabolism axis, and holds potential for translation to human AD.