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Previous studies report that (-)-epigallocatechin-3-gallate (EGCG),the most abundant polyphenolic ingredient in green tea,has high efficacy against Alzheimer’s disease (AD) in various in vivo and in vitro models.However,as a water-soluble component,how EGCG exerts its anti-AD effects in the brain was not elucidated.In the present study,we investigated the anti-AD mechanisms of EGCG in natural aging rats with cognitive impairments (CIs) assessed using Morris water maze.The rats were treated with EGCG (100 mg/kg per day,intragastrically) for 4 weeks.The expression of β-amyloid (Aβ1-42) in the brain was detected with immunohistochemical staining.We showed that EGCG administration significantly ameliorated the CI in the aging rats with CI and decreased Aβ1-42 plaque formation in their brains.Then we used an efficient ultra-performance liquid chromatography-tandem mass spectrometer method to evaluate EGCG concentrations in rat plasma and tissue distribution.We found that EGCG absorption was significantly increased in the aging with CI group compared with control young rats.After oral administration of EGCG (100 mg),EGCG could not be detected in the brain tissues of control young rats,but it was found in the brain tissue of aging rats with CI.By using Evans Blue assay,transmission electron microscopy,and West blotting assay,we demonstrated that the permeability of blood-brain barrier (BBB)was significantly increased in aging rats with CI.These results suggest that the permeability change of BBB is the physiological structural basis for EGCG treatment to improve leing and memory,thus providing a solid evidence for EGCG druggability in anti-AD therapeutic field.