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研究生：	程冠中 Cheng, Kuan-Chung
論文名稱：	探討Aβ誘導的提早死亡和行為改變相關的機制 The mechanisms for Aβ-induced behavioral changes and early death
指導教授：	姜學誠 Chiang, Hsueh-Cheng
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2021
畢業學年度：	110
語文別：	英文
論文頁數：	94
中文關鍵詞：	阿茲海默症、內質網壓力、表皮生長因子受體、β-澱粉樣蛋白、氧化壓力
外文關鍵詞：	Alzheimer's disease, ER stress, EGFR, Aβ, oxidative stress
相關次數：	點閱：156 下載：0
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阿茲海默症(AD)的特徵在於隨著年齡增加更容易產生學習和記憶障礙以及提早衰亡的現象。遺傳學研究發現β-澱粉樣蛋白(Aβ)的堆積是造成AD的主要元素之一。Aβ是由澱粉樣蛋白前趨蛋白(APP)經蛋白水解而成的產物。越來越多的證據表明Aβ是造成AD的主要原因，並且許多學者也致力於尋找降低大腦中Aβ堆積的方法。之前的研究中表明Aβ會誘發多種訊息路徑來造成不同的行為改變。然而，在Aβ降解或抑制Aβ生成的臨床試驗發現，減少腦中的Aβ堆積不足以改善AD的病程。這些的研究結果顯示著：(1) Aβ引起的AD病理機制仍然難以捉摸。(2) Aβ也會觸發一些即使在Aβ清除後仍然失調的機制。因此，我的研究重點是研究Aβ在整個AD的疾病發展進程中詳細的毒性機制。
本論文是以果蠅為實驗動物建立了Aβ所導致的病理模型。我的研究結果顯示不同的分子信號在不同的時間點單獨參與在Aβ所導致的不同的行為變化。早期Aβ的累積透過共同激活Ras和Pi3K的訊號來調節Rac1的活性導致記憶功能缺陷。然而，在早期的病程中，Aβ也會誘發XBP1的激活來促進細胞存活。在中期的Aβ病程中，更多的Aβ積累會強烈激活Pi3K-AKT訊號並誘發由蛋白酶體功能缺失所引起的PERK激活，從而誘導學習障礙。而在這個時候，需要同時減少Ras和Pi3K的訊號才可以恢復記憶功能的缺陷。在Aβ病程的後期，Aβ會誘發更複雜的訊息傳遞路徑，包括EGFR-Pi3K-AKT、Ras和InR 信號，來導致果蠅嚴重的學習障礙。
為了研究降低Aβ的堆積不足以改善AD的原因，我也建立了一個果蠅模型來研究Aβ堆積減少後的效應。我的研究顯示短暫的Aβ表達之後，即使Aβ的堆積在表達後很快降解，還是會導致晚年的學習障礙。我的研究結果也顯示早期的Aβ堆積會誘導還原酶、過氧化氫酶和dPrx5的減少來造成氧化壓力(ROS)的升高，從而誘導學習障礙並使細胞對氧化壓力更沒有抵抗力。早期增加XBP1或dPrx5的表達可以防止果蠅在Aβ清除後ROS的增加，提高學習性能，並保持細胞活力。此外，在Aβ停止表達後添加抗氧化劑像是維生素E、褪黑激素和硫辛酸，可以讓果蠅在Aβ清除後具有正常的學習能力。總言，我在果蠅上提供了Aβ病理的詳細機制。此外，我的研究提供了一個概念，就是往後對AD治療的研究不僅要針對Aβ本身的調控，也要調控Aβ所誘發的信號路徑。我的研究也提供了抗氧化劑和Aβ清除療法相結合的方法，可能成為未來AD的良好治療方法。

Alzheimer's disease (AD) is characterized by age-dependent cognitive impairment and lifespan shortening. Genetic studies provide a causative link between AD and beta-amyloid (Aβ) peptides, a proteolytic product of amyloid precursor protein (APP). Mounting evidence shows that Aβ is the primary cause of AD, and much effort has been spent on finding strategies to reduce Aβ accumulation in the brain. Previous studies have shown that Aβ triggers multiple signaling pathways to cause distinct behavioral changes. However, clinical trials focused on Aβ degradation or inhibition of Aβ production find that the reduction of Aβ accumulation in the brain is not enough to improve AD pathologies. The results of these studies suggest that (1) the mechanisms of AD pathologies caused by Aβ are still elusive. (2) Signaling pathway dysregulated by Aβ accumulates remains malfunction even after Aβ clearance. Therefore, my study focuses on investigating detailed mechanisms of Aβ toxicity and the progress of AD pathologies.
In this thesis, Drosophila is used to generate the model of Aβ pathologies. My findings show that the different molecular signaling is individually involved in different Aβ-induced behavioral changes in a time-dependent manner. Early Aβ accumulation regulates Rac1 activity by coactivating Ras and Pi3K signaling to induce memory deficits. However, Aβ triggers XBP1 activation to promote cell survival in the early stage of Aβ pathology. In the middle stage, more Aβ accumulation strongly activates Pi3K–AKT signaling and triggers PERK activation due to proteasome dysfunction to induce learning impairment. Furthermore, reduction of both Ras and Pi3K signaling is now required to recover memory deficit in this period. Finally, in the late stage of Aβ pathology, Aβ triggers more complex pathways, including epidermal growth factor receptor (EGFR)–Pi3K–AKT, Ras, and InR signaling, to cause severe learning impairment in Drosophila.
To investigate why Aβ reduction is not enough to improve AD, I also generate a fly model to the post-Aβ-clearance effects followed by the reduction of Aβ accumulation. My findings show that transient Aβ expression leads to learning impairment in later life, even though Aβ accumulation is degraded soon after the induction. My results also suggest that early Aβ expression reduced antioxidant enzyme expression, catalase, dPrx5, and elevated ROS accumulation to cause learning impairment and make cells less resistant to oxidative stress. On the other hand, early XBP1 or dPrx5 induction prevents ROS increment, improves learning performance, and preserves cell viability in the later life of the post-Aβ-clearance flies. Furthermore, the treatment of antioxidants, vitamin E, melatonin, and lipoic acid, after stops Aβ induction, prevented the learning impairment in post-Aβ-clearance flies in later life.
In summary, my study provides the detailed mechanism of Aβ pathologies in Drosophila. Furthermore, the thesis also provides the concept that targeting Aβ cascade and manipulating Aβ-triggered signaling pathways is the option for future AD treatment. In addition, my study also shows antioxidants are a good alternative medical intervention combined with Aβ clearance therapy for disease treatment in the future.

摘    要	I
Abstract	III
致謝	V
Abbreviation	VI
Table of contents	VII
List of figures	XI
Introduction	1
1 Introduction of Alzheimer's disease	1
2 Introduction of Amyloid-β and its pathology	2
3 The current challenge of AD	3
4 Receptor tyrosine kinase and its relationship with Alzheimer's disease	4
5 Endoplasmic reticulum (ER) stress and AD	6
6 Drosophila model	7
7 Specific aims	9
Materials and methods	10
1 Fly stocks	10
2 Pavlovian olfactory aversive conditioning	10
3 Western blot analysis	11
4 Survival assay	11
5 Quantitative RT-PCR	11
6 Brain Immunohistochemistry	12
7 Antioxidant feeding	13
8 Oxidative stress resistance	13
9 H2DCF staining	13
10 Image quantification	13
11 Statistical analysis	14
Results	15
1 Manipulation of AKT or FOXO improves Aβ-induced learning impairment but does not affect memory deficit.	15
2 Aβ-induced memory deficit is improved by the reduction of Pi3K or Rac1 activity.	16
3 Aβ-induced learning impairment followed by memory deficit is due to the cooperation of Ras-Rac1 and Pi3K-Rac1 signaling.	17
4 Reducing Pi3K and Ras is needed to improve memory deficit in the middle stage of Aβ pathology.	19
5 EGFR is the first receiver mediating Aβ-induced behavioral changes.	19
6 The improvement of Aβ-induced learning impairment in the late phase needs downregulation of both Ras and AKT signaling.	20
7 The improvement of Aβ-induced learning impairment in the late phase needs downregulation of both EGFR and InR signaling.	21
8 Reduced AKT but not Rac1 reverses Aβ-induced cell loss.	21
9 PERK activation is involved in Aβ-induced learning deficit, but not an early death.	22
10 Activated XBP1 improves Aβ-induced early death but not learning damage.	23
11 XBP1 activation is the early response to reflect Aβ accumulation.	24
12 The different activation periods between XBP1 and PERK are regulated by proteasome activity.	24
13 The Aβ-induced memory deficit improved by Aβ degradation but also led to learning impairment.	25
14 Overexpression of XBP1 for 3 days improved later life learning impairment in Aβ flies.	27
15 The activity of proteasome and autophagy did not involve in later life learning impairment in Aβ flies.	28
16 XBP1 regulated oxidative stress through dPrx5 to improve later life learning impairment in Aβ flies.	29
17 The reduction of ROS did not improve later life learning impairment with prolonged Aβ induction.	30
18 Early Aβ exposure makes the cell more unbearable to the oxidative stress in later life	30
Conclusion	32
Discussion	33
1 The different stages of AD pathology.	33
2 Different Pi3K signaling pathways cause memory and learning impairments induced by Aβ.	34
3 The involvement of different signaling pathways in a different stage of Aβ pathology.	34
4 Receptor tyrosine kinase is a potential therapeutic target for AD.	36
5 The survival signal is triggered in an early stage of Aβ pathology.	36
6 The Aβ-induced learning impairment is followed by memory deficit in Aβ flies.	36
7 The potential mechanisms for the time-sequential activation of XBP1 and PERK.	37
8 The potential biomarkers for Aβ pathologies.	37
9 The toxic mechanism of post Aβ clearance is different from continuous Aβ accumulation.	38
10 Existence of an endogenous Aβ degradation system in the fruit fly.	39
11 The application of my findings.	39
Figures and Figure legends	41
Reference	76
Appendix	92
                                    

Abeysinghe AADT, Deshapriya RDUS, Udawatte C. Alzheimer's disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci. 256:117996. (2020).
Agca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y. Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci. 17(1):46. (2016).
Anthony Jalin AMA, Jin R, Wang M, Li G. EPPS treatment attenuates traumatic brain injury in mice by reducing Aβ burden and ameliorating neuronal autophagic flux. Exp Neurol. 314:20-33. (2019).
Bader M, Benjamin S, Wapinski OL, Smith DM, Goldberg AL, Steller H. A conserved F box regulatory complex controls proteasome activity in Drosophila. Cell. 145(3):371-382. (2011).
Baulch JE, Acharya MM, Agrawal S, Apodaca LA, Monteiro C, Agrawal A. Immune and Inflammatory Determinants Underlying Alzheimer's Disease Pathology. J Neuroimmune Pharmacol. 15(4):852-862. (2020).
Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71(4):505-508. (2014).
Borin M, Saraceno C, Catania M, Lorenzetto E, Pontelli V, Paterlini A, Fostinelli S, Avesani A, Di Fede G, Zanusso G, Benussi L, Binetti G, Zorzan S, Ghidoni R, Buffelli M, Bolognin S. Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer's disease. Acta Neuropathol Commun. 6(1):61. (2018).
Bray MJC, Richey LN, Bryant BR, Krieg A, Jahed S, Tobolowsky W, LoBue C, Peters ME. Traumatic brain injury alters neuropsychiatric symptomatology in all-cause dementia. Alzheimers Dement. 17(4):686-691. (2021).
Britton JS, Lockwood WK, Li L, Cohen SM, Edgar BA. Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell. 2(2):239-249. (2002).
Carrillo-Mora P, Luna R, Colín-Barenque L. Amyloid beta: multiple mechanisms of toxicity and only some protective effects? Oxid Med Cell Longev. 2014:795375. (2014).
Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P. The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum Mol Genet. 20(11):2144-2160. (2011).
Chang KW, Zong HF, Rizvi MY, Ma KG, Zhai W, Wang M, Yang WN, Ji SF, Qian YH. Modulation of the MAPKs pathways affects Aβ-induced cognitive deficits in Alzheimer's disease via activation of α7nAChR. Neurobiol Learn Mem. 168:107154. (2020).
Chen L, Xu S, Liu L, Wen X, Xu Y, Chen J, Teng J. Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell Death Dis. 5(5):e1219. (2014).
Chen YR, Li YH, Hsieh TC, Wang CM, Cheng KC, Wang L, Lin TY, Cheung CHA, Wu CL, Chiang H. Aging-induced Akt activation involves in aging-related pathologies and Aβ-induced toxicity. Aging Cell. 18(4):e12989. (2019).
Cheng Y, Tian DY, Wang YJ. Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives. Transl Neurodegener. 9(1):16. (2020).
Chiang HC, Wang L, Xie Z, Yau A, Zhong Y. PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila. Proc Natl Acad Sci U S A. 107(15):7060-7065. (2010).
Cissé M, Duplan E, Lorivel T, Dunys J, Bauer C, Meckler X, Gerakis Y, Lauritzen I, Checler F. The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model. Mol Psychiatry. 22(11):1562-1575. (2017).
Cognigni P, Felsenberg J, Waddell S. Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila. Curr Opin Neurobiol. 49:51-58. (2018).
Corcoran KA, Lu Y, Turner RS, Maren S. Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease. Learn Mem. 9(5):243-252. (2002).
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-β peptide transport across the bloodbrain barrier and accumulation in brain. Nat Med. 9(7):907-13 (2003).
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug Memantine. J Biol Chem. 282(15):11590-11601. (2007).
d'Errico P, Meyer-Luehmann M. Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease. Front Aging Neurosci. 12:265. (2020).
De Strooper B, Karran E. The Cellular Phase of Alzheimer's Disease. Cell. 164(4):603-615. (2016).
Di Resta C, Ferrari M. New molecular approaches to Alzheimer's disease. Clin Biochem. 72:81-86. (2019).
Dickson DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Invest. 114(1):23-27. (2004).
Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR Jr. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 12(3):292-323. (2016).
Duffy JB. GAL4 system in Drosophila: a fly geneticist's Swiss army knife. Genesis. 34(1-2):1-15. (2002).
inelli A, Kelkar A, Song HJ, Yang H, Konsolaki M. A model for studying Alzheimer's Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci. 26(3):365-375. (2004).
Fonseca AC, Ferreiro E, Oliveira CR, Cardoso SM, Pereira CF. Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta. 1832(12):2191-2203. (2013).
Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol. 150(2):F23-30. (2000).
Garcia-Huerta P, Bargsted L, Rivas A, Matus S, Vidal RL. ER chaperones in neurodegenerative disease: Folding and beyond. Brain Res. 1648(Pt B):580-587. (2016).
Garner KL, Betin VMS, Pinto V, Graham M, Abgueguen E, Barnes M, Bedford DC, McArdle CA, Coward RJM. Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. Sci Rep. 8(1):3902. (2018).
Gärtner U, Holzer M, Arendt T. Elevated expression of p21ras is an early event in Alzheimer's disease and precedes neurofibrillary degeneration. Neuroscience. 91(1):1-5. (1999).
Godoy JA, Rios JA, Zolezzi JM, Braidy N, Inestrosa NC. Signaling pathway cross talk in Alzheimer's disease. Cell Commun Signal. 12:23. (2014).
Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease. EMBO Mol Med. 5(1):52-63. (2013).
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297(5580):353-356. (2002).
Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W. The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol. 174(4):1241-1251. (2009).
Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W. The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol. 110(2):165-172. (2005).
Huang HC, Tang D, Lu SY, Jiang ZF. Endoplasmic reticulum stress as a novel neuronal mediator in Alzheimer's disease. Neurol Res. 37(4):366-374. (2015).
Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 27(1):18. (2020).
Huang Y, Wan Z, Wang Z, Zhou B. Insulin signaling in Drosophila melanogaster mediates Aβ toxicity. Commun Biol. 2:13. (2019).
Husemann J, Loike JD, Kodama T, Silverstein SC. Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar β-amyloid. J Neuroimmunol. 114(1-2):142-50. (2001).
Iijima-Ando K, Hearn SA, Granger L, Shenton C, Gatt A, Chiang HC, Hakker I, Zhong Y, Iijima K. Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. J Biol Chem. 283(27):19066-19076. (2008).
Iijima K, Iijima-Ando K. Drosophila models of Alzheimer's amyloidosis: the challenge of dissecting the complex mechanisms of toxicity of amyloid-beta 42. J Alzheimers Dis. 15(4):523-540. (2008).
Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y. Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A. 101(17):6623-6628. (2004).
Inaki M, Vishnu S, Cliffe A, Rørth P. Effective guidance of collective migration based on differences in cell states. Proc Natl Acad Sci U S A. 109(6):2027-2032. (2012).
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 9(11):e111898. (2014).
Jacob L, Azouvi P, Kostev K. Age-Related Changes in the Association Between Traumatic Brain Injury and Dementia in Older Men and Women. J Head Trauma Rehabil. 36(3):E139-E146. (2020).
Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM. Amyloid-β Receptors: The Good, the Bad, and the Prion Protein. J Biol Chem. 291(7):3174-3183. (2016).
Ji XR, Cheng KC, Chen YR, Lin TY, Cheung CHA, Wu CL, Chiang HC. Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies. FASEB J. 32(3):1375-1387. (2018).
Jiang L, Mao R, Zhou Q, Yang Y, Cao J, Ding Y, Yang Y, Zhang X, Li L, Xu L. Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory. Mol Neurobiol. 2016 Mar;53(2):1247-1253. (2016).
Joe E, Ringman JM. Cognitive symptoms of Alzheimer's disease: clinical management and prevention. BMJ. 367:l6217. (2019).
Kadowaki H, Nishitoh H. Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes (Basel). 4(3):306-333. (2013).
Kamat PK, Kalani A, Rai S, Swarnkar S, Tota S, Nath C, Tyagi N. Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies. Mol Neurobiol. 53(1):648-661. (2016).
Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y. Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci. 30(11):3924-3932. (2010).
Kang K, Ryoo HD, Park JE, Yoon JH, Kang MJ. A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development. PLoS One. 10(5):e0126795. (2015).
Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M. Induction of neuronal death by ER stress in Alzheimer's disease. J Chem Neuroanat. 28(1-2):67-78. (2004).
Kelley BJ, Petersen RC. Alzheimer's disease and mild cognitive impairment. Neurol Clin. 25(3):577-609. (2007).
Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ. Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science. 341(6152):1399-1404. (2013).
Kirouac L, Rajic AJ, Cribbs DH, Padmanabhan J. Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease. eNeuro. 4(2):ENEURO.0149-16.2017. (2017).
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 27(4):796-807. (2007)
Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A. 100(17):9946-9951. (2003).
Lee JH, Won SM, Suh J, Son SJ, Moon GJ, Park UJ, Gwag BJ. Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice. Exp Mol Med. 42(5):386-394. (2010).
Levenga J, Wong H, Milstead RA, Keller BN, LaPlante LE, Hoeffer CA. AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity. Elife. 6:e30640. (2017).
Li JQ, Tan L, Wang HF, Tan MS, Tan L, Xu W, Zhao QF, Wang J, Jiang T, Yu JT. Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease: a systematic review and meta-analysis of cohort studies. J Neurol Neurosurg Psychiatry. 87(5):476-84. (2016).
Li S, Yang L, Selzer ME, Hu Y. Neuronal endoplasmic reticulum stress in axon injury and neurodegeneration. Ann Neurol. 74(6):768-777. (2013).
Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, Glavic A, Kress C, Lin JH, Walter P, Reed JC, Glimcher LH, Hetz C. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell. 33(6):679-691. (2009).
Liu Y, Du S, Lv L, Lei B, Shi W, Tang Y, Wang L, Zhong Y. Hippocampal Activation of Rac1 Regulates the Forgetting of Object Recognition Memory. Curr Biol. 26(17):2351-2357. (2016).
Liu YH, Wang YR, Xiang Y, Zhou HD, Giunta B, Mañucat-Tan NB, Tan J, Zhou XF, Wang YJ. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery. Mol Neurobiol. 51(1):1-7. (2015).
Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 179(2):312-339. (2019).
Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA. REST and stress resistance in ageing and Alzheimer's disease. Nature. 507(7493):448-454. (2014).
Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS. Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers Dement. 7(5):532-539. (2011).
Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci. 16(9):1299-1305. (2013).
MacDonald CL, Schwarze N, Vaishnavi SN, Epstein AA, Snyder AZ, Raichle ME, Shimony JS, Brody DL. Verbal memory deficit following traumatic brain injury: assessment using advanced MRI methods. Neurology. 71(15):1199-1201. (2008).
Madhusudhan T, Wang H, Dong W, Ghosh S, Bock F, Thangapandi VR, Ranjan S, Wolter J, Kohli S, Shahzad K, Heidel F, Krueger M, Schwenger V, Moeller MJ, Kalinski T, Reiser J, Chavakis T, Isermann B. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat Commun. 6:6496. (2015).
Manterola L, Hernando-Rodríguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellón L, Alberdi E, Cavaliere F, Lacerda HM, Jimenez S, Parada LA, Matute C, Zugaza JL. 1-42 β-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry. 3(1):e219. (2013).
Magdesian MH, Carvalho MM, Mendes FA, Saraiva LM, Juliano MA, Juliano L, Garcia-Abreu J, Ferreira ST. Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. J Biol Chem. 283(14):9359-9368. (2008).
Martín-Peña A, Rincón-Limas DE, Fernandez-Fúnez P. Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer's disease. Sci Rep. 8(1):9915. (2018).
Martínez G, Vidal RL, Mardones P, Serrano FG, Ardiles AO, Wirth C, Valdés P, Thielen P, Schneider BL, Kerr B, Valdés JL, Palacios AG, Inestrosa NC, Glimcher LH, Hetz C. Regulation of Memory Formation by the Transcription Factor XBP1. Cell Rep. 14(6):1382-1394. (2016).
McGuire SE, Mao Z, Davis RL. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci STKE. 2004(220):pl6. (2004a).
McGuire SE, Roman G, Davis RL. Gene expression systems in Drosophila: a synthesis of time and space. Trends Genet. 20(8):384-391. (2004b).
Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease. J Neurochem. 136(3):457-474. (2016).
Morgan AR, Touchard S, Leckey C, O'Hagan C, Nevado-Holgado AJ; NIMA Consortium, Barkhof F, Bertram L, Blin O, Bos I, Dobricic V, Engelborghs S, Frisoni G, Frölich L, Gabel S, Johannsen P, Kettunen P, Kłoszewska I, Legido-Quigley C, Lleó A, Martinez-Lage P, Mecocci P, Meersmans K, Molinuevo JL, Peyratout G, Popp J, Richardson J, Sala I, Scheltens P, Streffer J, Soininen H, Tainta-Cuezva M, Teunissen C, Tsolaki M, Vandenberghe R, Visser PJ, Vos S, Wahlund LO, Wallin A, Westwood S, Zetterberg H, Lovestone S, Morgan BP; Annex: NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease. Inflammatory biomarkers in Alzheimer's disease plasma. Alzheimers Dement. 15(6):776-787. (2019).
M Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, de Leon MJ. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur J Nucl Med Mol Imaging. 36(5):811-822. (2009).
Mota SI, Costa RO, Ferreira IL, Santana I, Caldeira GL, Padovano C, Fonseca AC, Baldeiras I, Cunha C, Letra L, Oliveira CR, Pereira CM, Rego AC. Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease. Biochim Biophys Acta. 1852(7):1428-1441. (2015).
Nakagawa Y, Reed L, Nakamura M, McIntosh TK, Smith DH, Saatman KE, Raghupathi R, Clemens J, Saido TC, Lee VM, Trojanowski JQ. Brain trauma in aged transgenic mice induces regression of established abeta deposits. Exp Neurol. 163(1):244-252. (2000).
Nemetz PN, Leibson C, Naessens JM, Beard M, Kokmen E, Annegers JF, Kurland LT. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am J Epidemiol. 149(1):32-40. (1999).
Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, Marino R, Federici M, De Bartolo P, Aversa D, Dell'Acqua MC, Cordella A, Sancandi M, Keller F, Petrosini L, Puglisi-Allegra S, Mercuri NB, Coccurello R, Berretta N, D'Amelio M. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease. Nat Commun. 8:14727. (2017).
Nunziante M, Ackermann K, Dietrich K, Wolf H, Gädtke L, Gilch S, Vorberg I, Groschup M, Schätzl HM. Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein. J Biol Chem. 286(39):33942-33953. (2011).
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 39(3):409-421. (2003).
Ohnishi T, Yanazawa M, Sasahara T, Kitamura Y, Hiroaki H, Fukazawa Y, Kii I, Nishiyama T, Kakita A, Takeda H, Takeuchi A, Arai Y, Ito A, Komura H, Hirao H, Satomura K, Inoue M, Muramatsu S, Matsui K, Tada M, Sato M, Saijo E, Shigemitsu Y, Sakai S, Umetsu Y, Goda N, Takino N, Takahashi H, Hagiwara M, Sawasaki T, Iwasaki G, Nakamura Y, Nabeshima Y, Teplow DB, Hoshi M. Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proc Natl Acad Sci U S A. 112(32):E4465-E4474. (2015).
Ordonez DG, Lee MK, Feany MB. α-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton. Neuron. 97(1):108-124.e6. (2018).
Owusu-Ansah, E., Yavari, A., Banerjee, U. A protocol for in vivo detection of reactive oxygen species. Protocol Exchange. 10. (2008).
Ozben T, Ozben S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease. Clin Biochem. 72:87-89. (2019).
Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 447(7146):859-863. (2007).
Parri HR, Hernandez CM, Dineley KT. Research update: α7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol. 82(8):931-942. (2011).
Pearce MMP, Spartz EJ, Hong W, Luo L, Kopito RR. Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat Commun. 6:6768. (2015).
Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H, Tsujio I, Takeda M, Alafuzoff I, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K. Role of protein kinase B in Alzheimer's neurofibrillary pathology. Acta Neuropathol. 105(4):381-392. (2003).
Perry S, Kiragasi B, Dickman D, Ray A. The Role of Histone Deacetylase 6 in Synaptic Plasticity and Memory. Cell Rep. 18(6):1337-1345. (2017).
Prasanthi JR, Larson T, Schommer J, Ghribi O. Silencing GADD153/CHOP gene expression protects against Alzheimer's disease-like pathology induced by 27-hydroxycholesterol in rabbit hippocampus. PLoS One. 6(10):e26420. (2011).
Raby CA, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Emmerling MR. Traumatic brain injury increases beta-amyloid peptide 1-42 in cerebrospinal fluid. J Neurochem. 71(6):2505-2509. (1998).
Radyuk SN, Michalak K, Klichko VI, Benes J, Rebrin I, Sohal RS, Orr WC. Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila. Biochem J. 419(2):437-445. (2009).
Ray A, Speese SD, Logan MA. Glial Draper Rescues Aβ Toxicity in a Drosophila Model of Alzheimer's Disease. J Neurosci. 37(49):11881-11893. (2017).
Reas ET, Hagler DJ Jr, White NS, Kuperman JM, Bartsch H, Cross K, Loi RQ, Balachandra AR, Meloy MJ, Wierenga CE, Galasko D, Brewer JB, Dale AM, McEvoy LK. Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer's disease. Alzheimers Res Ther. 9(1):55. (2017).
Reinhardt S, Schuck F, Grösgen S, Riemenschneider M, Hartmann T, Postina R, Grimm M, Endres K. Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease. FASEB J. 28(2):978-997. (2014).
Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 11(6):1114-1125. (2001).
Rickle A, Bogdanovic N, Volkman I, Winblad B, Ravid R, Cowburn RF. Akt activity in Alzheimer's disease and other neurodegenerative disorders. Neuroreport. 15(6):955-959. (2004).
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 8(7):519-529. (2007).
Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease. Nature. 531(7595):508-512. (2016).
Ruggiano A, Foresti O, Carvalho P. Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol. 204(6):869-879. (2014).
Ryoo HD, Domingos PM, Kang MJ, Steller H. Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J. 26(1):242-252. (2007).
Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J. ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology. J Neuroinflammation. 6:41. (2009).
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 8(6):595-608. (2016).
Shuai Y, Lu B, Hu Y, Wang L, Sun K, Zhong Y. Forgetting is regulated through Rac activity in Drosophila. Cell. 140(4):579-589. (2010).
Smith LM, Strittmatter SM. Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity. Cold Spring Harb Perspect Med. 7(5):a024075. (2017).
Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, LaFerla FM, Kiyohara Y, Iwaki T, Kira J. Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease. Curr Alzheimer Res. 10(1):11-20. (2013).
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly ofa Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 11(2):155-161. (2010).
Sui L, Wang J, Li BM. Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem. 5(10):762-776. (2008).
Tajiri N, Kellogg SL, Shimizu T, Arendash GW, Borlongan CV. Traumatic brain injury precipitates cognitive impairment and extracellular Aβ aggregation in Alzheimer's disease transgenic mice. PLoS One. 8(11):e78851. (2013).
Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, and Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction. Proc Natl Acad Sci U S A. 106(47):20021-20026. (2009)
Tonoki A, Kuranaga E, Tomioka T, Hamazaki J, Murata S, Tanaka K, Miura M. Genetic evidence linking age-dependent attenuation of the 26S proteasome with the aging process. Mol Cell Biol. 29(4):1095-1106. (2009).
Tully T, Preat T, Boynton SC, Del Vecchio M. Genetic dissection of consolidated memory in Drosophila. Cell. 79(1):35-47. (1994).
Tully T, Quinn WG. Classical conditioning and retention in normal and mutant Drosophila melanogaster. J Comp Physiol A. 157(2):263-277. (1985).
Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron. 79(5):887-902. (2013).
Vargas LM, Leal N, Estrada LD, González A, Serrano F, Araya K, Gysling K, Inestrosa NC, Pasquale EB, Alvarez AR. EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PLoS One. 9(3):e92309. (2014).
van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 21(1):21-35. (2020).
Vincenz L, Jäger R, O'Dwyer M, Samali A. Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 12(6):831-843. (2013).
Wang L, Chiang HC, Wu W, Liang B, Xie Z, Yao X, Ma W, Du S, Zhong Y. Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc Natl Acad Sci U S A. 109(41):16743-16748. (2012).
Wang L, Liang B, Zhong Y. Reduced EGFR level potentially mediates the Aβ42-induced neuronal loss in transgenic fruit fly and mouse. Protein Cell. 4(9):647-649. (2013).
Wu W, Du S, Shi W, Liu Y, Hu Y, Xie Z, Yao X, Liu Z, Ma W, Xu L, Ma C, Zhong Y. Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer's disease. Protein Cell. 10(10):745-759. (2019).
Wu Z, Wang ZH, Liu X, Zhang Z, Gu X, Yu SP, Keene CD, Cheng L, Ye K. Traumatic brain injury triggers APP and Tau cleavage by delta-secretase, mediating Alzheimer's disease pathology. Prog Neurobiol. 185:101730. (2020).
Yang ST, Hsiao IT, Hsieh CJ, Chiang YH, Yen TC, Chiu WT, Lin KJ, Hu CJ. Accumulation of amyloid in cognitive impairment after mild traumatic brain injury. J Neurol Sci. 349(1-2):99-104. (2015).
Zhang M, Han N, Jiang Y, Wang J, Li G, Lv X, Li G, Qiao Q. EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78. Cancer Med. 7(12):6234-6246. (2018).
Zhang MZ, Wang Y, Paueksakon P, Harris RC. Epidermal growth factor receptor inhibition slows progression of diabetic nephropathy in association with a decrease in endoplasmic reticulum stress and an increase in autophagy. Diabetes. 63(6):2063-2072. (2014).
Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 22(1):246-260. (2008).
Zuroff L, Daley D, Black KL, Koronyo-Hamaoui M. Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci. 74(12):2167-2201. (2017).

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