Potential Natural Products for Alzheimer’s Disease: Targeted Search Using the Internal Ribosome Entry Site of Tau and Amyloid-β Precursor Protein

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.

Endogenous Conjugation of Biomimetic Dinitrosyl Iron Complex with Protein Vehicles for Oral Delivery of Nitric Oxide to Brain and Activation of Hippocampal Neurogenesis

“…When the hidden platform is removed during the probe trial, the duration for the aging mice staying in the target quadrant provides a quantitative evaluation on the ability of spatial learning and memory. 67 In comparison with the CD group, a significant decrease of duration in the target region displayed by aging mice in the WD group supports the cognitive impairment that resulted from Western diet-induced metabolic syndrome ( Figure 5 f). Of importance, a daily treatment of DNIC-1 improves the cognitive impairment in aging mice with metabolic syndrome based on the increase of the duration in the target region featured by WD:NO group ( p = 0.217 in comparison with WD group).…”

“…It depends on distal cues to crossing from start locations around the perimeter of an open swimming arena to locate a hidden escape platform. , During the acquisition phase of training (days 1–5 during week 17), all groups display a progressive decrease in latency to reach the hidden platform (Figure S16). When the hidden platform is removed during the probe trial, the duration for the aging mice staying in the target quadrant provides a quantitative evaluation on the ability of spatial learning and memory . In comparison with the CD group, a significant decrease of duration in the target region displayed by aging mice in the WD group supports the cognitive impairment that resulted from Western diet-induced metabolic syndrome (Figure f).…”

A Review of Fermented Foods with Beneficial Effects on Brain and Cognitive Function

“…A study demonstrated that fermented ginseng reversed memory impairment and reduced Aβ accumulation in the AD mouse model (50). Another study reported that NB34, a preparation of fermented Radix notoginseng , can serve in an alike functional manner to memantine, a drug used for the treatment of AD, by reducing the activities of both tau internal ribosome entry site and APP (51). …”

Production and Application of Multicistronic Constructs for Various Human Disease Therapies

“…It is of interest to create multicistronic vector-based test systems for screening potential compounds for the treatment of neurodegenerative diseases. An example of such a test system is the human neuroblastoma cell line co-expressing APP and TAU genes separated by IRES and designed for the screening of AD therapy drugs [69,70]. Using the above test system, curcumin, its structural analogue demethoxycurcumin [69], and memantine (non-competitive NMDA receptor antagonist ( N -methyl- d -aspartate)) [70] have been able to inhibit APP and TAU IRES-dependent translation initiation.…”