碩士 / 輔仁大學 / 營養科學系碩士班 / 103 / Alzheimer’s disease (AD) is the most common degenerative dementia. β-amyloid protein (Aβ), neurofibrillary tangles (NFTs, consisted of tau protein) deposit and mitochondrial dysfunction in hippocampus and cortex is the pathology of Alzheimer’s disease (AD). It has been known that folate supplementation can improve mitochondrial function and it can decrease AD risk factor. However, most patients were detected that they suffered from AD until late-stage of AD. Whether folate supplementation in this stage can improve mitochondrial shape and function then further decrease AD development is unclear. Therefore, we would like to investigate whether change folate intake can decrease Aβ and NFTs deposits, improve mitochondrial shape and mitochondrial function then improve AD pathology. It has two parts in our experiment. The first part we used 11months C57BL/6 mice as control group (nonTg, saline 200μl/day) and the same age of 3xTg-AD mice divided into transgenic group (Tg, saline 200μl/day) and transgenic folate supplementation group (Tg+FS, folate drinking water 3 mg/dl and folate gavage 1.2 mg/kg/day). After 4 months, we used L.casei to determine folate levels of brain cortex, liver and serum; used ELISA to analyze cortical Aβ40, Aβ42 and tau pS199 deposition; used western blotting to detect phosphorylated tau (ptau), proCaspase-9, mitofusin 1 (Mfn1), dynamin-related protein 1 (Drp1), voltage-dependent anion channel 1 (VDAC1), kinesin light chain 1 (KLC1) and complex IV protein expression in cortex and liver; used Seahorse XF-24 metabolic flux to analyze mitochondrial respiratory function in brain; used transmission electron microscope (TEM) to observed mitochondrial morphology and myelin shape; used Morris water maze to detect cognitive function. We compared Tg group with nonTg group, it showed Aβ40, Aβ42 and ptau deposition in brain cortex in Tg group was significantly more than nonTg group; it had lower proCaspase-9 expression in brain cortex; it had higher Mfn1 expression in brain cortex and liver; Drp1 expression in brain cortex was significantly decreased. Otherwise, we also observed whether folate supplementation can improve these symptoms, so we compared Tg+FS group with Tg group. It demonstrated folate levels in brain cortex, liver and serum in Tg+FS group was significantly higher than Tg group; ptau expression in cortex and liver was decreased; proCaspase-9 expression in cortex was increased; it had lower Mfn1 expression in cortex and liver; it had higher Drp1 expression in cortex; mitochondrial shape and myelin shape were integrity. The overall in three groups, we found it had significantly negative correlation between brain cortex folate level and Aβ40 deposition in brain cortex (r= -0.988, p= 0.012); it had significantly negative correlation between liver folate level and the slope of learning (r=-0.44, p= 0.04). In the second part, we used the same age of C57BL/6 mice divided into three group, Control group (saline 200μl/day), low folate intake group (LF, 0.2 mg folic acid/kg diet and saline 200μl/day) and folate supplement group (Tg+FS, folate drinking water 3 mg/dl and folate gavage 1.2 mg/kg/day). After 4 months, to compared LF group and Control group, it showed LF group ptau expression was higher than Control group in cortex and liver; it had lower proCaspase-9 expression in brain cortex; Drp1 expression in brain cortex and liver were significantly increased; mitochondrial shape was fission and elongation and myelin was disrupted in brain cortex and hippocampus. We also investigated whether folate supplementation had imprve capability, so compared FS group and LF group. We found folate level in cortex, liver and serum in FS group were significantly higher than LF group; it had lower Drp1 expression in cortex and liver; mitochondrial shape and myelin shape were integrity. The overall in three groups, we found it had significantly negative correlation between brain and liver folate level and the slope of learning (r= -0.744, p= 0.009; r=-0.548, p= 0.028). In conclusion, it showed increasing folate intake, it has higher folate level in mice, and it may decrease Aβ and ptau protein production, decrease apoptosis, regulate mitochondrial morohology, and it folate level getting higher, cognitive function was better. Further, it may regulate ageing related AD pathological, mitochondrial abnormalities and cognitive function.
| Identifer | oai:union.ndltd.org:TW/102FJU00513014 |
| Date | January 2014 |
| Creators | Chou, Chien-Yu, 周千祐 |
| Contributors | Rwei-Fen S. Huang, Chen, Ta-Fu, 許瑞芬, 陳達夫 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 147 |
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