Scope: Astaxanthin (AST) is ubiquitous in aquatic foods and microorganisms. The study previously finds that docosahexaenoic acid-acylated AST monoester (AST-DHA) improves cognitive function in Alzheimer's disease (AD), although the underlying mechanism remains unclear. Moreover, autophagy is reportedly involved in amyloid-β (Aβ) clearance and AD pathogenesis. Therefore, this study aims to evaluate the preventive effect of AST-DHA and elucidates the mechanism of autophagy modulation in Aβ pathology.
Methods and results: In the cellular AD model, AST-DHA significantly reduces toxic Aβ1-42 levels and alleviated the accumulation of autophagic markers (LC3II/I and p62) in Aβ25-35 -induced SH-SY5Y cells. Notably, AST-DHA restores the autophagic flux in SH-SY5YmRFP-GFP-LC3 cells. In APP/PS1 mice, a 3-month dietary supplementation of AST-DHA exceeded free-astaxanthin (F-AST) capacity to increase hippocampal and cortical autophagy. Mechanistically, AST-DHA restores autophagy by activating the ULK1 signaling pathway and restoring autophagy-lysosome fusion. Moreover, AST-DHA relieves ROS production and mitochondrial stress affecting autophagy in AD. As a favorable outcome of restored autophagy, AST-DHA mitigates cerebral Aβ and p-Tau deposition, ultimately improving neuronal function.
Conclusion: The findings demonstrate that AST-DHA can rectify autophagic impairment in AD, and confer neuroprotection in Aβ-related pathology, which supports the future application of AST as an autophagic inducer for maintaining brain health.
Keywords: astaxanthin; autophagosome-lysosome fusion; autophagy; mitochondria; neuronal function.
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