藉由APP/PS1基因轉殖小鼠探討跑步機運動對於阿茲海默氏症之影響

Abstract

阿茲海默氏症(Alzheimer’s disease, AD)為一漸進式的神經退化性疾病，主要發生於老年的族群。此疾病在神經病理方面有兩個最主要的特徵，其一為由乙型類澱粉蛋白(amyloid-beta, Aβ)堆積所形成的老年斑塊(senile plaque)；另一則為τ蛋白(tau protein)經由過度磷酸化累積所形成的神經纖維糾結(neurofibrillary tangles, NFTs)。這些神經病理的特徵與慢性發炎反應，氧化壓力或是神經傳導物質失調都有密切的關連；而過去的許多研究中已指出運動對於腦部與認知功能可經由多方途徑達到有益的效果。因此本實驗採用C3H/HeJ× C57BL/6J品系年老(21-24個月)與年輕(7-8個月)的APP/PS1基因轉殖鼠及野生型老鼠，進行為期四週的跑步機運動或是不運動之處理。結果發現，運動提升了年輕基因轉殖鼠的探索能力，且經由血清中皮質酮(corticosterone)濃度測定也發現運動顯著性減少皮質酮的量。於認知及行為能力方面，運動選擇性增加年輕的APP/PS1基因轉殖鼠的探索能力及改善年老的APP/PS1基因轉殖鼠於長期記憶的獲得與存取，但是對於短期記憶並無影響。於病理分析部分，運動亦顯著性地減少年輕APP/PS1老鼠腦部無法分解的Aβ42/Aβ40比值，年老APP/PS1老鼠血糖增加；同時，運動亦可回復APP/PS1基因轉殖鼠腦中血清素神經(serotonergic neuron, 5-HT)的含量。綜合上述實驗結果，為期四週無壓力的跑步機運動對於本實驗中的APP/PS1基因轉殖鼠，的確可以選擇性改善行為、認知功能以及部分病理上的表現。

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting the elderly population. Two primary features were characterized for the disease, plaques composed of aggregate amyloid-beta (Aβ) and neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau protein. These neuropathologies are closely linked with chronic inflammation, oxidative stress and neurotransmitter dysregulation. Many evidences show that exercise is beneficial to the brain and cognitive function through multiple pathways. Therefore, the present studies conducted moderate, no shock treadmill running exercise on aged (21~ 24 months) and young (7~ 8 months) APP/PS1 transgenic and littermate male mice for four weeks. Age matched sedentary groups were also included in this study. Exercise enhanced exploratory behavior in young APP/PS1 transgenic mice and decreased the level of the serum corticosterone. In addition, moderate exercise improved only the spatial reference learning and memory, not spatial working memory or exploratory behavior in aged APP/PS1 transgenic mice. The results from pathologic analysis show exercise decreased the level of the insoluble Aβ42/Aβ40 ratio in young APP/PS1 transgenic mice. Exercise increased the blood glucose (BG) level in aged APP/PS1 transgenic mice. Furthermore, exercise also increased the level of the serotonergic immunoreactive neurons in the APP/PS1 transgenic mice. In summary, we found that moderate, non-shock treadmill exercise can selective improve behavior, cognitive performance and the pathogenic phenotypes in the APP/PS1 transgenic mice.