Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by progressive memory loss and synaptic dysfunctions. Converging lines of evidence suggest that soluble oligomeric amyloid-beta (Aβ) contributes substantially to the synaptic loss in AD. Our group previously demonstrated that Eph receptor A4 (EphA4) mediates neurotoxicity of Aβ and that its activation impairs synaptic transmission and long-term potentiation. Importantly, oral administration of rhynchophylline (Rhy), a novel EphA4 inhibitor found in a Chinese medicinal herb (Uncaria rhynchophylla), improves synaptic impairment in APP/PS1 mice, an AD transgenic mouse model. To understand the mechanism by which Rhy exerts its beneficial effect, we conducted DNA microarray technology to analyze the transcriptome...[ Read more ]

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by progressive memory loss and synaptic dysfunctions. Converging lines of evidence suggest that soluble oligomeric amyloid-beta (Aβ) contributes substantially to the synaptic loss in AD. Our group previously demonstrated that Eph receptor A4 (EphA4) mediates neurotoxicity of Aβ and that its activation impairs synaptic transmission and long-term potentiation. Importantly, oral administration of rhynchophylline (Rhy), a novel EphA4 inhibitor found in a Chinese medicinal herb (Uncaria rhynchophylla), improves synaptic impairment in APP/PS1 mice, an AD transgenic mouse model. To understand the mechanism by which Rhy exerts its beneficial effect, we conducted DNA microarray technology to analyze the transcriptome in the brains of APP/PS1 mice after Rhy treatment. A panel of candidate genes was identified to be upregulated in APP/PS1 mouse brains when compared to the wild-type controls. Accordingly, Rhy treatment restored the transcription levels of these genes to the wild-type control level. Gene ontology analysis revealed that these genes participate in innate and adaptive immunity. Among these candidates, Spp1 was one of the most differentially expressed genes in both comparisons and thus was selected for further characterization. The gene and protein regulation of Spp1 in APP/PS1 mouse brains after the Rhy treatment was verified by quantitative real-time PCR and ELISA respectively. Moreover, its protein expression increased significantly in APP/PS1 mice from 11 to 13 months of age, suggesting a correlation between Spp1 expression and AD progression. In addition, Aβ induced Spp1 production and secretion in cortical neuronal culture. This may explain the source of its elevated level in APP/PS1 mice. Together, these findings highlighted that Spp1 may be modulated by Rhy and it may contribute to the pathogenesis of AD.