The Protective Effects of Edible Folic Acid and Medicinal Folinic Acid on Late-Stage Triple-Transgenic Alzheimer's Old Mice Hearts

• Main Authors: Yi-Chen Su, 蘇易辰
• Other Authors: You-Liang Hsieh
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/59825918692849063223

碩士 === 亞洲大學 === 保健營養生技學系 === 103 === PART I Alzheimer’s disease and cardiovascular disease share some risk factors. Many experimental and clinical studies showed the involvement of cardiovascular disease-related pathways in Alzheimer’s disease. Persons with Alzheimer’s disease also displayed a higher risk of incident ischemic heart disease. In this study, we apply triple-transgenic late-stage Alzheimer's (AD) mice to examine the heart function changes, in order to explore the relationship between Alzheimer's disease and Cardiovascular diseases. The triple-transgenic late-stage Alzheimer's (AD) mice (3xTg-AD; PS1M146V, APPSwe, and tauP301L) were fed with folic acid (FA) and folinic acid (FN) to study their effects in protecting hearts. Groups of sixteen-month old triple-transgenic late-stage AD mice weighing between 34–65 g were randomly allocated into three groups; AD, AD plus FA, and AD plus FN. Mice were gastric fed with FA or FN once daily at 12 mg/kg body weight (BW). There body weights were assessed throughout the trial. Mice were sacrificed using carbon dioxide suffocation after sixteen months. The experimental result found that body weight, whole heart weight, and left ventricle weight were proportional reduce among the AD+ FA, and AD+ FN groups as compared to ADgroup. The excised hearts measured by Western blotting indicated reduction of hypertrophy proteins p-p38 and p-c-jun were more significant in FA treated mice group, but p-GATA4, ANP and BNP were strongly reduced in the group of AD+FN. Besides, the reduction of uPA, MMP-9, MMP-2, MEK 1/2 and SP-1 fibrosis proteins were also observed in the hearts of both AD+FA and AD+FN mice and more strongly reduced in the group of AD+FN (Fig. 4). In summary, the results indicated that FA or FN could exert anti-cardiac hypertrophy and fibrosis to protect the hearts of triple-transgenic Alzheimer's old mice. PART II Cardiomyocytes undergoing apoptosis have been found in a variety of pathological conditions such as dilated cardiomyopathy, ischemia/reperfusion injury, myocardial infarction and end-stage heart failure. Evidences suggest that Alzheimer’s disease and cardiovascular disease share some risk factors, and persons with Alzheimer’s disease had a higher risk of incident ischemic heart disease; however, the mechanisms involved in Alzheimer’s disease and cardiac cell apoptosis still remains unclear. In this study, we apply sixteen-month old triple-transgeniclate (3xTg-AD;PS1M146V, APPSwe, and tauP301L ) late-stage Alzheimer's (AD) mice, which were fed with folic acid (FA) and folinic acid (FN) to study their effects in preventing cardiac cell apoptosis and heart disease. Groups of sixteen-month old triple-transgenic late-stage AD mice weighing between 34–65 g were randomly allocated into three groups; AD, AD plus FA, and AD plus FN. Mice were gastric fed with FA or FN once daily at 12 mg/kg body weight (BW). Mice were sacrificed using carbon dioxide suffocation after sixteen months. Our result from excised heart tissues indicated that reduced of intercellular space and maintain cardiac cell morphology were observed both in FA and FN treated mice hearts and stronger reduced in FN treatment. Moreover, the AD groups had a greater number of TUNEL-positive cardiac cells than the other groups. In western blotting results showed more reduction of FAS/L and C-Caspase-3 in FA treated mice, but FADD and Caspase-8 were strongly reduced in FN treated mice. For mitochondria-dependent apoptotic pathway, the reduction of apoptosis proteins were both observed in the hearts of FA and FN treated AD mice. BAK and C-Caspase-9 was more reduction in FN group, but C-Caspase-3 and Cytochrome-c reduced more in FA group. Enhancement of survival proteins p-IGF1R, p-PI3K p-AKT, Bcl-XL, Bcl2 and longevity SIRT1 signaling proteins, p-AMPK-α, SIRT1, PGC1-α, p-FOXO3 were both observed in FA and FN treated mice and even more strongly enhanced in FN grouop. This study observed that the ingestion of FA or FN caused a reduction of apoptosis proteins and enhancement of survival and SIRT1 signaling proteins in the hearts. Collectively, our results suggest that FA or FN could inhibit heart damage via promote cardiac cell survival and prevent apoptosis in triple-transgenic late-stage AD aging mice.