臺灣博碩士論文加值系統

近年來腸-腦軸及腸道菌的重要性逐漸提升，腸道菌相失衡已經被證實和氣喘、肥胖、憂鬱症、自閉症、帕金森氏症及阿茲海默氏症等疾病高度相關。阿茲海默症是會使記憶功能缺損及行為改變的神經退化性疾病，至今仍然缺乏有效的治療方式。腸道菌的多樣性以及細菌代謝物都可能和阿茲海默症有關，但能否透過飲食調控腸道菌相的組成，改善患者的認知功能仍未定論。此研究中，我們使用益生質(TCP)、共生質(益生質及益生菌混和物TCP+P)進行研究。我們發現阿茲海默氏症小鼠經過共生質餵食，展現較佳的學習能力及空間記憶能力，並且增加神經新生的能力，同時降低全身性發炎反應及小鼠海馬迴中類澱粉蛋白的沉積量。我們的研究顯示共生質對阿茲海默氏症小鼠具有保護性作用，具有透過日常營養補充品減緩阿茲海默氏症疾病進程的效果。

The concept of gut-brain axis and importance of gut microbiota have been raised these years. Dysbiosis of gut microbiota is associated with multiple disorders, including asthma, obesity, depression, autism, Parkinson’s disease and Alzheimer’s disease (AD). AD is a neurodegenerative disease that impairs multiple memory and behavior domains without any effective treatment. Whether microbiota modulation can ameliorate cognitive function in AD remains unknown. In our study, we established prebiotics and synbiotic mixture, TCP and TCP+P, as intervention for AD mouse model. Our results demonstrated that after synbiotic treatment for 2 months, AD mice showed improving spatial memory, and increasing neurogenesis compared to untreated mice. Furthermore, the synbiotic treatment also reduced systemic inflammation, Aβ 42 accumulation and plaque formation.
Taken together, our study demonstrated the protective effects of synbiotic mixture in AD mice, suggesting that dietary modulation may be a potential treatment to slow down AD processing.

誌謝..........................................................................................i
摘要.........................................................................................ii
Abstract....................................................................................iii
Contents.....................................................................................iv
Figure index................................................................................vii
Introduction..................................................................................1
Alzheimer’s disease (AD).....................................................................1
Genetics......................................................................................2
hAPP transgenic mouse model...................................................................2
Gut-brain axis and gut microbiota.............................................................3
The changes of gut microbiota composition in AD...............................................3
Microbiota-induced inflammation in AD.........................................................4
Bacteria-derived amyloids.....................................................................5
Probiotics, prebiotics, and synbiotics........................................................6
Hypothesis and aims...........................................................................8
Materials and methods.........................................................................9
Animals.......................................................................................9
TCP+P mixture.................................................................................9
TCP mixture..................................................................................10
Fecal DNA preparation........................................................................10
16S rRNA gene sequencing.....................................................................10
Open field...................................................................................11
Novel object recognition test................................................................12
Morris water maze............................................................................12
Enzyme-linked immunosorbent assay (ELISA)....................................................12
Immunohistochemistry.........................................................................13
Microbiota composition analysis..............................................................13
Statistical analysis.........................................................................14
Results......................................................................................15
Synbiotic mixture ameliorated cognitive impairment in APP mouse model........................15
Prebiotic mixture had no effect on cognitive functions in APP mouse model....................19
Both prebiotics and synbiotic mixtures did not improve object recognition
memory in APP mouse model....................................................................22
Synbiotic mixture did not alter anxiety-related behavior and locomotor
activity in APP mouse model..................................................................24
Prebiotics mixture did not alter anxiety-related behavior and locomotor
activity in APP mouse model..................................................................27
Synbiotic mixture significant decreased Aβ42 level in hippocampus of APP mouse model........30
Both prebiotics and synbiotic mixture significantly decreased β-sheet
structures amyloid in the hippocampus of APP mouse model.....................................32
Neither prebiotics nor synbiotics mixtures could reduce astrocyte-related
inflammatory reaction in the hippocampus of APP mouse model..................................35
Both prebiotics and synbiotics did not alter Iba-1 positive microglia
expression in the hippocampus of APP mouse model.............................................38
Synbiotic mixture reduced local and systemic inflammation in APP mouse model.................41
Synbiotic mixtures induced neurogenesis in the hippocampus of APP mouse model................45
Synbiotic mixtures alter gut microbiota composition in APP mouse model.......................48
Discussion...................................................................................51
Human and mice gut microbiota composition....................................................51
Factors influencing the composition of mice gut microbiota...................................52
Morris water maze test for learning and memory deficits......................................53
Effects of probiotics treatment on behavioral deficits.......................................54
Effects of synbiotics treatment in neuroinflammation.........................................54
The efficacy and safety of probiotics in human...............................................55
The ability of probiotic bacteria colonization...............................................55
Possible mechanisms of probiotics affect Alzheimer’s disease................................56
The inhibitory effects of synbiotics on tumor development....................................57
The effects of synbiotics in Alzheimer’s disease............................................58
Conclusion...................................................................................59
References...................................................................................60
Appendix.....................................................................................75
Supplementary information....................................................................77
主座標分析（PCoA, Principal Co-ordinates Analysis）..........................................77
系統演化多樣性分析(Phylogenetic Diversity)...................................................77
相對豐富度(Relative Abundance)...............................................................78
各組別腸道菌相對豐富度之p value..............................................................79


Figure index
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Fig. 11_40
Fig. 12_42
Fig. 13_44
Fig. 14_47
Fig. 15_49
Fig. 16_50

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