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

ScopeAstaxanthin (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-beta (A beta) clearance and AD pathogenesis. Therefore, this study aims to evaluate the preventive effect of AST-DHA and elucidates the mechanism of autophagy modulation in A beta pathology.Methods and resultsIn the cellular AD model, AST-DHA significantly reduces toxic A beta 1-42 levels and alleviated the accumulation of autophagic markers (LC3II/I and p62) in A beta 25-35-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 A beta and p-Tau deposition, ultimately improving neuronal function.ConclusionThe findings demonstrate that AST-DHA can rectify autophagic impairment in AD, and confer neuroprotection in A beta-related pathology, which supports the future application of AST as an autophagic inducer for maintaining brain health. Docosahexaenoic acid-acylated astaxanthin monoester (AST-DHA) exceeds free-astaxanthin (F-AST) capacity to restore autophagic impairment of Alzheimer's disease. The mechanistic studies find that AST-DHA restores autophagy by activating the ULK1 signaling pathway and rescuing autophagy-lysosome fusion. As a favorable consequence of enhanced autophagy, AST-DHA mitigates cerebral A beta and p-Tau deposition, ultimately improving neuronal function.image