Abstract
Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by β-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 μM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the β-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE−/−) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD.
Highlights
Alzheimer’s disease (AD) is considered as the most common neurodegenerative malady in the modern but senile society [1]
We report that the NMDA receptor antagonist, memantine can suppress the expression of neuronal amyloid precursor protein (APP) and tau proteins through the novel cap-independent translational initiation mechanism
We constructed bi-cistronic plasmids to monitor the activity of the 5'-UTR of both the APP and tau as well as to verify the neurotropism of these IRESes
Summary
Alzheimer’s disease (AD) is considered as the most common neurodegenerative malady in the modern but senile society [1]. Since it has been shown that many cellular mRNAs contain IRESes, it is likely that up to 10% of all mRNAs have the capability to initiate translation by the cap-independent mechanism [18,19]. We report that the NMDA receptor antagonist, memantine can suppress the expression of neuronal APP and tau proteins through the novel cap-independent translational initiation mechanism. Based on this observation, we employed the IRESes of APP and Tau as the potential targets for AD to screen Lactobacillus spp. fermented traditional Chinese herbs and identified a preparation that can inhibit the translational activity of the Tau IRES.
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