阿茲海默症佔失智病狀中的多數，其伴隨的症狀為記憶力的喪失以及大腦內含有Tau蛋白累積與Aβ斑塊的形成。Tau為微管蛋白，主要表現於中樞神經系統內以穩定神經軸突。先前研究證實了在果蠅眼睛內同時表現Tau以及AD易感性基因會導致果蠅眼睛的受損。然而Tau的磷酸化與阿茲海默症易感受基因的相互關係尚未釐清。因此在本研究中使用果蠅作為生物實驗模型工具，探討阿茲海默症易感受基因與Tau。結合GAL4/UAS系統，探討Crag-RNAi與Tau共同表現於多巴胺神經元內以觀察其影響。此外，我們發現共同表現Crag-RNAi/Tau除了使多巴胺神經元內的磷酸化Tau表現量增加外，也會使粒線體的表現量增多。我們統整了在Crag表現量降低情況下，磷酸化Tau與粒線體當中有著某種關聯性。

Majority of patients with Alzheimer's disease (AD) suffer from dementia with symptoms of loss of memory and accumulation of Tau protein and Aβ plaques could be found in brains. Tau is a microtubule-associated protein (MAPT) that mainly expressed in the central nervous system to stabilize axons. Previous experiments had demonstrated that the expression of Tau and AD susceptibility genes in the eyes of Drosophila could lead to the impairing of eyes. However, the relationship between Tau hyperphosphorylation and AD susceptibility genes remains a mystery. Therefore, Drosophila was chosen as the model organism in this study to explore the relationship between AD susceptibility genes and Tau. With GAL4 / UAS system, the influences of co-expressing Crag-RNAi and Tau in the dopaminergic neurons could be investigated. Furthermore, we found that co-expression of Crag-RNAi/Tau increased the levels of phosphorylated Tau as well as mitochondria in the dopaminergic neurons. It could be concluded from this study that certain correlation between phosphorylated Tau and mitochondria in knockdown of Crag does exist

Introduction 1
Alzheimer’s disease and Parkinson's disease 1
Tau hypothesis 2
Dopaminergic neurons and Parkinson's disease 4
Glutamatergic neurons and Alzheimer’s disease 4
DENN/MADD 5
Mitochondria and Neurodegeneration 6
Drosophila melanogaster 7
Materials & Methods 9
Fly strains 9
Drosophila maintenance 9
Immunohistochemistry analysis 9
Results 11
AD susceptibility genes show interaction with tau. 11
Knockdown of Crag increased Tau-induced dopaminergic neurodegeneration in
1-week old and 3-week old flies. 12
Knockdown of Crag can enhance the level of phosphorylation Tau in dopaminergic neurons. 13
The level of mitochondria under co-expression of Tau/Crag-RNAi was more than
the control group during aging... 15
During aging, co-expression of Tau/Crag-RNAi could make mitochondria translocate to the axon... 16
The expression of Crag-RNAi could change the shape and number of glutamatergic neuron.. 17
The effects of Crag-RNAi expressed on glutamatergic neurons cause more damage
than DA neurons 18
Discussion 20
Knockdown of Crag and dopaminergic neurons. 21
Phosphorylated Tau and mitochondria under co-expression of Tau and
Crag RNAi. 22
Knockdown of Crag and glutamatergic neurons. 23
Tau and TNF1 signaling. 24
Over-expression of Crag in neurons. 25
Reference 27
Figures 33
Fig. 1 AD associated genes modify tau expression in fly eyes 34
Fig. 2 Expression of crag-RNAi enhanced Tau-induced neurodegeneration in dopaminergic neurons. 36
Fig. 3 Co-expression of Tau、Crag-RNAi in dopaminergic neurons show the level of phosphorylation Tau is more higher than only expression of Tau in week1 and week3. 38
Fig. 4 Co-expression of Crag-RNAi, Tau in dopaminergic neurons enhanced distribution of mitochondria during aging.. 40
Fig. 5 Co-expression of Tau, Crag-RNAi in dopaminergic neurons show that relationship between phosphorylation of Tau and mitochondria. 42
Fig. 6 Crag-RNAi expression induced loss of glutamatergic neurons 45
Fig. 7 The effect of Crag-RNAi expressed on different neurons in 1-week, 3-weeks, and 7-weeks old fly. 47
Fig. 8 AD associated MADD and possible affected mechanisms. 49

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