阿茲海默症是目前最常見的一種神經退化性疾病。Amyloid beta 42 (Aβ42)胜肽被認為在其致病機轉中扮演了重要的角色。先前研究發現早期症狀的發生主要與麩氨酸神經元和膽鹼性神經元功能異常有關，然而這些異常可能與Aβ42有關。因此，本篇研究利用果蠅做為模式生物來探究Aβ42對這兩種神經系統之影響。我們發現將Aβ42表現於麩氨酸神經元中會先造成過量的麩氨酸囊泡釋放，隨後引起突觸及神經元的退化，且造成果蠅壽命減短及運動能力下降。同樣地，Aβ42也引發麩氨酸神經元之退化。除此之外，我們也去探討Aβ42 和微管蛋白tau間是否有交互作用，發現tau會加強Aβ42 所引起的神經毒性。總結以上結果，此Aβ42果蠅也許能做為一個阿茲海默症模型來研究其中致病之分子機制，希望對此疾病有著更進一步的了解並找出新的治療方向。

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common cause of dementia in the elderly people. Amyloid beta 42 peptide (Aβ42) is the primary constituent of amyloid plaques, a major pathological hallmark of AD. It is well known that the dysfunction in both cholinergic and glutamatergic systems contribute to the symptomatology of AD, but the exact causes remain unclear. Here, we use Drosophila as a model system to examine the effects of overexpression of the human Aβ42 peptides on the populations of glutamatergic and cholinergic neurons. The expression of Aβ42 resulted in an initially increased glutamate neurotransmission, and subsequently Aβ42 led to an age-dependent progressive degeneration of neurons. The neurodegeneration was accompanied by defects in locomotion activity and decreased longevity. Similarly, flies overexpressing Aβ42 in cholinergic neurons cause an age-dependent neurodegeneration, and shortened lifespan. Moreover, we found that there may be an interaction between Aβ42 and wild-type tau protein. Taken together, our flies may serve as an early-onset model to understand molecular mechanisms underlying Aβ toxicity and to discover the new therapeutic targets for AD.

Acknowledgement I
Abstract II
摘要 III
List of Figures V
Introduction 1
 Alzheimer’s disease 1
 The glutamatergic neurons and Alzheimer's disease 2
 The cholinergic neurons and Alzheimer's disease 4
Materials and Methods 6
 Drosophila genetics and stocks 6
 Immunohistochemistry and confocal images 6
 Behavioral analysis 7
 Lifespan assay 7
 Scanning electron microscopy 7
Results 8
 Human Aβ42 overexpression in the glutamatergic neurons shortened lifespan 8
 Expression of human Aβ42 resulted in an early-onset degeneration of glutamatergic neurons. 10
 Human Aβ42 overexpression caused an age-dependent decrease in glutamatergic neurotransmission 14
 Overexpression of human Aβ42 in cholinergic neurons caused an early defects in locomotion and lifespan. 17
 Human Aβ42 induced an age-dependent neurodegeneration of cholinergic neurons 19
 Tau protein exacerbates the neurotoxicity caused by human Aβ42 expression 21
Discussion 25
References 28

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Braak, H., & Braak, E. (1998). Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl, 53, 127-140.
Cavallucci, V., D'Amelio, M., & Cecconi, F. (2012). Abeta toxicity in Alzheimer's disease. Mol Neurobiol, 45(2), 366-378. doi: 10.1007/s12035-012-8251-3
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