碩士 / 輔仁大學 / 營養科學系碩士班 / 104 / It has been known that folic acid supplements can reduce the abnormal accumulation of Aβ and neurofibrillary tangles and further improve mitochondrial shape and function. In addition, previous studies had observed in folic acid supplementation can reverse the brain cortex and hippocampus area of myelin damage in AD mice, and improve cognitive function. However, the mechanism of folic acid status on the abnormal formation of myelin and mitochondria in the brain remains unclear.Thus this study aim to investigate whether supplementation of folinic acid (FN) and folic acid (FA) may ameliorate Alzheimer’s disease (AD)-associated pathological development using the 3xTg transgenic mice as the experimental model. In the first part, forty 3xTg-AD mice of 16 month-old were divided into three groups fed with the AIN93M diet in the absence (Control) or presence of FA and FN supplements (12 mg/kg/day by force feeding) for 3 months. After sacrifice, hippocampus of mice undergo RNA extraction and genome-wide cDNA microarray analysis as well as analyze protein expression level of myelin and mitochondrial related proteins by western blotting. Genomic expression profiles of mice hippocampus show that 112 genes (8.6%) were significantly modulated by FA treatment and 996 genes (12.4%) modulated by FN treatment according to the stringent criteria as compared to the pooled control (P < 0.05 and > 2-fold changes, three replicates).Wherein193 genes up-regulated and 803 genes down-regulated in TgFN group, 32 genes up-regulated and 80 genes down-regulated in TgFA group. Neuroactive ligand-acceptor interaction in cathepsin G (CTSG) significant up-regulated 28 fold in TgFN group. PPAR pathway in fatty acid binding protein1( FABP1 ) significant down-regulated 79 fold. FA-modified AD gene expression profiles overlapped with FN-modified profiles in complement and coagulation cascades. Fibrinogen gamma chain (Fgg), fibrinogen beta chain (Fgb), coagulation factor II (F2), plasminogen (Plg), complement component factor I (Cfi),kininogen 1(Kng1), coagulation factorⅩ(F10) 及serine (or cysteine) peptidase inhibitor (Serpine) families were significant regulation. Both of MBP levels in TgFN, TgFA group were significantly higher than Tg groups. Phosphate-tau, Drp1, VDAC and Mfn1 protein levels in TgFN, TgFA group were significantly lower than those of Tg group. Next, to observe the effects of folate supplementation in midlife of AD. 11months 3xTg-AD mice divided into transgenic group (Tg, saline 200μl/day) and transgenic folate supplementation group (TgFS, folate drinking water 3 mg/dl and folate gavage 1.2 mg/kg/day) and the same age of non-transgene mice C57BL/6 mice (non-Tg control) for 4 months. After sacrifice, hippocampus of mice undergo RNA extraction and genome-wide cDNA microarray analysis as well as analyze protein expression level of myelin and mitochondrial related proteins by western blotting.Whole genome microarray analysis was compared for nonTg group and Tg group. Results showed that several biological pathways were regulated by AD mice, including cell adhesion molecules (CAMs), focal adhesion, cytokine-cytokine receptor interaction, complement and coagulation cascades, neuroactive ligand-receptor interaction and long-term depression. Wherein 7 genes up-regulated and 8 genes down-regulated. Comparison for Tg group and TgFS group, three biological pathways were regulated by folate. CNTNAP2(1.6 fold), ESAM(1.7 fold) and SCD4(-5.9 fold) in CAMs. VEGFA(1.7 fold), PTEN(2.0 fold), FLT1(1.8 fold) and ITGA1( 1.8 fold) in focal adhesion. VEGFA(1.7fold), PPBP(2.5 fold)and TNFSF10(1.7 fold) in cytokine-cytokine receptor interaction. Both of MBP levels in Tg, TgFS group were significantly lower than nonTg groups and 18.5 kDa MBP in TgFS group was significantly higher than Tg group. PTEN, Akt protein level in TgFS group was significantly lower than nonTg group. Taken together, folinc acid and folic acid supplementation in mid and late stage of AD can reduce the phosphorylation tau generate and maintain myelin integrity, to regulate and delay age-related development of Alzheimer's disease pathology. Both forms of folate down regulation of the complement and coagulation cascade pathways related genes, reduced clotting factors leading thrombus generation, thereby improving AD pathologic process.
| Identifer | oai:union.ndltd.org:TW/104FJU00513007 |
| Date | January 2016 |
| Creators | JHENG YU, 鄭瑜 |
| Contributors | SHIU,RWEI-FEN, 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 | 97 |
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