title: 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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan. yun9350751@hotmail.com.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Tasi
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan 32032, Taiwan. tychin@cycu.edu.tw.|Program and Center of Nanoscience Technology, Chung Yuan Christian University, Taoyuan 32032, Taiwan. tychin@cycu.edu.tw.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chin
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan 32032, Taiwan. assam217@yahoo.com.tw.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: New Bellus Enterprise Co., Ltd., Tainan 72042, Taiwan. john@newbellus.com.tw.
authors.forename: Chun-Chih
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. sllee@mail.cmu.edu.tw.
authors.forename: Shou-Lun
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan 32032, Taiwan. tywu@cycu.edu.tw.|Program and Center of Nanoscience Technology, Chung Yuan Christian University, Taoyuan 32032, Taiwan. tywu@cycu.edu.tw.
authors.forename: Tzong-Yuan
authors.initials: TY
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002491:Central Nervous System Agents / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D000067556:Internal Ribosome Entry Sites; D008297:Male; D008559:Memantine / Q000494:pharmacology; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009928:Organ Specificity; D065853:Spatial Learning / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D002491:Central Nervous System Agents; D004365:Drugs, Chinese Herbal; D000067556:Internal Ribosome Entry Sites; D016875:tau Proteins; D008559:Memantine