Docosahexaenoic Acid‐Acylated Astaxanthin Monoester Ameliorates Amyloid‐β Pathology and Neuronal Damage by Restoring Autophagy in Alzheimer's Disease Models

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 Aβ 1‐42 levels and alleviated the accumulation of autophagic markers (LC3II/I and p62) in Aβ 25‐35 ‐induced SH‐SY5Y cells. Notably, AST‐DHA restores the autophagic flux in SH‐SY5Y mRFP‐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.