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.

Adlard PA, Perreau VM, Cotman CW (2005a) The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging 26:511-520.
Adlard PA, Perreau VM, Pop V, Cotman CW (2005b) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci 25:4217-4221.
Allsop D, Landon M, Kidd M (1983) The isolation and amino acid composition of senile plaque core protein. Brain Res 259:348-352.
Ari Z, Kutlu N, Uyanik BS, Taneli F, Buyukyazi G, Tavli T (2004) Serum testosterone, growth hormone, and insulin-like growth factor-1 levels, mental reaction time, and maximal aerobic exercise in sedentary and long-term physically trained elderly males. Int J Neurosci 114:623-637.
Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939-945.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57:695-703.
Chen S, Zhang XJ, Li L, Le WD (2007) Current experimental therapy for Alzheimer's disease. Curr Neuropharmacol 5:127-134.
Churchill JD, Galvez R, Colcombe S, Swain RA, Kramer AF, Greenough WT (2002) Exercise, experience and the aging brain. Neurobiol Aging 23:941-955.
Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295-301.
Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464-472.
Davies P (1988) Neurochemical studies: an update on Alzheimer's disease. J Clin Psychiatry 49 Suppl:23-28.
Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT (2009) Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J 23:2459-2466.
Franklin CA, Karkeck J (1989) Weight loss and senile dementia in an institutionalized elderly population. J Am Diet Assoc 89:790-792.
Garcia-Capdevila S, Portell-Cortes I, Torras-Garcia M, Coll-Andreu M, Costa-Miserachs D (2009) Effects of long-term voluntary exercise on learning and memory processes: dependency of the task and level of exercise. Behav Brain Res 202:162-170.
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704-706.
Gortz N, Lewejohann L, Tomm M, Ambree O, Keyvani K, Paulus W, Sachser N (2008) Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice. Behav Brain Res 191:43-48.
Gulve EA (2008) Exercise and glycemic control in diabetes: benefits, challenges, and adjustments to pharmacotherapy. Phys Ther 88:1297-1321.
Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 12:383-388.
Hayes K, Sprague S, Guo M, Davis W, Friedman A, Kumar A, Jimenez DF, Ding Y (2008) Forced, not voluntary, exercise effectively induces neuroprotection in stroke. Acta Neuropathol 115:289-296.
Hooijmans CR, Blom HJ, Oppenraaij-Emmerzaal D, Ritskes-Hoitinga M, Kiliaan AJ (2009) S-adenosylmethionine and S-adenosylhomocysteine levels in the aging brain of APP/PS1 Alzheimer mice. Neurol Sci 30:439-445.
Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI (2006) Compulsive exercise acutely upregulates rat hippocampal brain-derived neurotrophic factor. J Neural Transm 113:803-811.
Huang HJ, Liang KC, Chen CP, Chen CM, Hsieh-Li HM (2007) Intrahippocampal administration of A beta(1-40) impairs spatial learning and memory in hyperglycemic mice. Neurobiol Learn Mem 87:483-494.
Huang HJ, Liang KC, Chang YY, Ke HC, Lin JY, Hsieh-Li HM (2009) The interaction between acute oligomer Abeta(1-40) and stress severely impaired spatial learning and memory. Neurobiol Learn Mem.
Janus C (2004) Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem 11:337-346.
Jolivalt CG, Hurford R, Lee CA, Dumaop W, Rockenstein E, Masliah E (2009) Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp Neurol.
Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature 331:530-532.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973-977.
Liu YF, Chen HI, Yu L, Kuo YM, Wu FS, Chuang JI, Liao PC, Jen CJ (2008) Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice. Neurobiol Learn Mem 90:81-89.
Liu YF, Chen HI, Wu CL, Kuo YM, Yu L, Huang AM, Wu FS, Chuang JI, Jen CJ (2009) Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol 587:3221-3231.
Lu B, Chow A (1999) Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res 58:76-87.
Maccioni RB, Rojo LE, Fernandez JA, Kuljis RO (2009) The role of neuroimmunomodulation in Alzheimer's disease. Ann N Y Acad Sci 1153:240-246.
Martin JB (1999) Molecular basis of the neurodegenerative disorders. N Engl J Med 340:1970-1980.
Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW (2009) Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimers Dement 5:287-294.
Nichol KE, Parachikova AI, Cotman CW (2007) Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav Brain Res 184:124-132.
Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW (2008) Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation 5:13.
Nishida Y, Ito S, Ohtsuki S, Yamamoto N, Takahashi T, Iwata N, Jishage K, Yamada H, Sasaguri H, Yokota S, Piao W, Tomimitsu H, Saido TC, Yanagisawa K, Terasaki T, Mizusawa H, Yokota T (2009) Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. J Biol Chem 284:33400-33408.
Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, Sun X, Zhao L, Yu M, Xu Z, Dong W, Qin Y, Fei G, Zhong C, Xu TL (2010) Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain 133:1342-1351.
Parachikova A, Cotman CW (2007) Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease. Neurobiol Dis 28:143-153.
Parachikova A, Nichol KE, Cotman CW (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 30:121-129.
Perez CA, Cancela Carral JM (2008) Benefits of physical exercise for older adults with Alzheimer's disease. Geriatr Nurs 29:384-391.
Pietropaolo S, Sun Y, Li R, Brana C, Feldon J, Yee BK (2009) Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse model. Behav Neurosci 123:181-195.
Porayette P, Gallego MJ, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS (2009) Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J Biol Chem 284:23806-23817.
Ragozzino ME, Parker ME, Gold PE (1992) Spontaneous alternation and inhibitory avoidance impairments with morphine injections into the medial septum. Attenuation by glucose administration. Brain Res 597:241-249.
Tanaka S, Nakamura S, Ueda K, Kameyama M, Shiojiri S, Takahashi Y, Kitaguchi N, Ito H (1988) Three types of amyloid protein precursor mRNA in human brain: their differential expression in Alzheimer's disease. Biochem Biophys Res Commun 157:472-479.
Thathiah A, De Strooper B (2009) G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease. Sci Signal 2:re8.
Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, Hwang DY, Cho JY (2008) Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model. Int J Mol Med 22:529-539.
Veeraraghavalu K, Choi SH, Zhang X, Sisodia SS (2010) Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling. J Neurosci 30:6903-6915.
Ward RV, Davis JB, Gray CW, Barton AJ, Bresciani LG, Caivano M, Murphy VF, Duff K, Hutton M, Hardy J, Roberts GW, Karran EH (1996) Presenilin-1 is processed into two major cleavage products in neuronal cell lines. Neurodegeneration 5:293-298.
White H, Pieper C, Schmader K, Fillenbaum G (1996) Weight change in Alzheimer's disease. J Am Geriatr Soc 44:265-272.
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513-517.