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Soluble amyloid-␤ (A␤) oligomers (A␤Os), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since A␤Os are a key therapeutic target, we attempted to identify natural agents that reduce A␤O neurotoxicity. Using an assay system in which primary cultured neurons are treated with A␤Os, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited A␤O-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast,