Soluble amyloid-β (Aβ) oligomers (AβOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since AβOs are a key therapeutic target, we attempted to identify natural agents that reduce AβO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AβOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AβO-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, tyrosol administration did not affect Aβ accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AβO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.
Keywords: Alzheimer’s disease; amyloid-β; neuron; oligomer; oxidative stress; synapse.