The impact of decreased folate content in brain to the occurrence of Alzheimer’s Disease-like neuropathies and pathogenesis in aged zebrafish

  • 朱 家儀

Student thesis: Master's Thesis

Abstract

Folate also known as vitamin B9 participates in various physiological functions including nucleotides biosynthesis amino acid metabolism neurotransmitters synthesis and S-adenosylmethionine formation Folate is crucial for intracellular methylation potential cell proliferation and differentiation Folate deficiency often causes neural tube defects in fetus Folate deficiency is also considered a risk factor for Alzheimer’s Disease (AD) in the elderly However the pathomechanism underlying the folate-related AD remains unclear to date hampering the development and application of folate-involving preventive/therapeutic regimen against AD The aim of this study is to investigate how folate deficiency contributes to the occurrence of AD Previously a transgenic zebrafish line with inducible folate deficiency was developed in our lab With this transgenic line and the modified T-maze device we showed that the aged fish (1 5 to 2 year-old) with decreased folate content in brain displayed impeded cognitive and memory ability Immunohistochemical staining revealed the accumulation of both amyloid plaques and Tau accumulations in the brain cryo-sections prepared from these folate deficient aged fish The RT-PCR with the cDNA prepared from the folate deficient embryos and the brain of folate deficient aged fish revealed a decreased expression of cathepsin B a cysteine proteases in lysosome Increased oxidative stress was observed in both folate deficient embryos and fish brain tissues Decreasing intracellular folate content also decreased cathepsin B transcript increased acidic vesicles accumulations and increased LC3 punctas in human neuroblastoma SKnSH cells All the above-described abnormalities in cells were partly reversed by adding antioxidant or folate to the culture medium Here we showed that the aged transgenic zebrafish with potential folate deficiency in brain displayed pathological characteristics of AD similar to those observed in mammals Also folate deficiency might contribute to the AD-like pathogenesis via decreasing cathepsin B expression and the interplay between the interfered intracellular autophagic-lysosomal pathway and increased oxidative stress Future studies will be focused on evaluating the preventive efficacy of different folate adducts with/without combinatorial strategies using this folate deficient transgenic zebrafish model
Date of Award2014 Aug 22
Original languageEnglish
SupervisorTzu-Fun Fu (Supervisor)

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