隨著醫學進步，人類平均壽命延長，慢性疾病逐漸成為現代公共衛生的重要議題。阿滋海默症為老年失智人口最主要族群，去年全球失智人口總數約為四千五百萬，阿滋海默症約佔失智總人口百分之七十五。隨著老年人口急劇增加，阿滋海默症帶來的社會負擔將不容小覷。

目前仍未有生物指標可精確診斷疾病進程，也沒有治療方法可將疾病治癒。增加對疾病的認識以減緩阿滋海默症即將帶來的衝擊，乃現今各國研究的重要方針。類澱粉蛋白異常堆疊是目前阿滋海默症的主要致病假說，然而近二十年來針對類澱粉蛋白的治療皆未能通過臨床試驗。本論文僅針對在台灣家族中找到的兩個導致早發型家族阿茲海默症的突變進行研究，以探討任何可能導致阿滋海默症的相關病理機轉，希望能藉此對未來研究方向有所幫助。

關於類澱粉前驅蛋白D678H突變，我們發現它不正常增加類澱粉蛋白的產生、聚集以及細胞毒性，並增加與金屬離子的螯合及寡倍體的產生。此研究再次驗證類澱粉蛋白的重要性，同時首次為金屬離子螯合劑應用在治療上提供基因佐證。關於presenilin-1 G206D突變，我們發現它不正常增加具毒性類澱粉蛋白的比例，並進一步使內質網中鈣離子濃度異常升高，然而在溶酶體中鈣離子濃度未受明顯影響且自噬小體也能正常代謝。此外，G206D降低presenilin與Pen2親和度、蛋白質穩定性以及在內質網的表現量。此研究除再度証實類澱粉蛋白重要性，也指出探討內質網的鈣離子調控將對疾病的致病機轉有助益。最後，在眾多阿滋海默症的相關致病機轉中，彼此一直缺乏連結性。我們的研究也指出蛋白質在細胞中的座落位置是決定其功能性的關鍵，可用來暗示不同的病理現象。因此，探討類澱粉前驅蛋白或是presenilin中負責調控蛋白質在細胞間運輸的氨基酸將對疾病的致病機轉有助益。 

Alzheimer’s disease (AD), the most common form of dementia, has a worldwide prevalence over 5% in people age 65 and older. There is no cure for the disease, which results in a heavy social burden. Around 0.1% of the AD cases are early-onset (before age 65) familial forms of the autosomal dominant inheritance, attributed to mutations in one of the three genes: those encoding amyloid precursor protein (APP), and presenilin-1 (PS1) and -2 (PS2). Genetic predisposition provides a powerful tool to reveal the pathogenic mechanisms of the disease.

Our group characterizes pathogenic mechanisms of two mutations, encoding APPD678H and PS1G206D mutants, found in Taiwanese pedigrees. One of the pathogenic hallmarks of the disease is the amyloid plaque, in which abnormal concentrated amyloid beta (Aβ) peptide and metal ions deposit. Aβ peptide, product of APP cleaved by γ-secretase, is currently considered to be the major trigger of the disease. PS1 is the catalytic component of the γ-secretase complex and Pen2 is a critical co-factor for γ-secretase activity.

APPD678H has an additional metal ion-coordinating residue, histidine (H). We speculate that this mutation may promote susceptibility of Aβ to ions. We found that the D678H mutation increases Aβ production and prolonged Aβ oligomer state with higher neurotoxicity. D678H also increases Aβ susceptibility to zinc and copper, which lead to altered aggregation pathway. Therefore, our study not only characterizes the D678H mutant Aβ aggregation pathway in detail, but also first time provides a genetic evidence for the importance of zinc and copper in the disease.

PS1G206D provides an additional polar transmembrane-based amino acid, aspartate (D), near the Pen2 binding site. We speculate that this mutation may interfere with the Pen2 binding and PS1 functions. We found that the G206D mutation decreases PS1-Pen2 interaction, but does not abolish γ-secretase activity. For γ-secretase dependent function, the G206D mutation alters the proportion of Aβ varieties, but does not alter Notch cleavage. For γ-secretase independent function, this mutation disrupts the calcium homeostasis but not endo-lysosomal functions. Therefore, our study not only characterizes the general functions of PS1 G206D mutant in detail, but also fir the first time provides genetic evidence for the importance of PS1-Pen2 interaction in the disease.

Together, genetic tool helps us to dissect the pathogenic mechanism in cellular models and that could further provide therapeutic target for the disease. We highlight the importance of Aβ-ions and PS1-Pen2 interaction in AD pathology.

Contents
Acknowledgment (Chinese)--- i
Abstract (Chinese)-------------- ii
Abstract (English)----------- iii
Publications and Presentations----- iv
List of Abbreviations----------- vii
List of Figures------------------ ix

Chapter 1. General Introduction------------------------ 1

1.1 Alzheimer’s disease (AD)………………………………… 2
Prevalence
Pathologic Hallmark
Genetics
1.2 Familial Alzheimer’s disease (FAD).………. 3
Amyloid Precursor Protein (APP)
Presenilin (PS)
Mechanism
1.3 Medications for Alzheimer’s disease…………….. 6
Current options
Anti-amyloid strategy
Aβ-directed immunotherapy to promote amyloid clearance
Targeting β-secretase or γ-secretase to reduce Aβ production
Challenges for clinical trials
Prevention for AD
1.4 Motivation and Goal……………………………… 10

Chapter 2. Amyloid Precursor Protein (APP) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-Zinc/Copper Assemblies---------- 12

2.1 Introduction…………………………………………… 13
Localization of APP mutations
Aβ aggregation
Metal ions in Alzheimer’s disease
Aβ-metal interaction
APP D678H mutation
2.2 Method………………………………………………… 16
Human subject
Materials
Plasmids
Cell culture
APP and Aβ measurement
Aβ preparation
Photo-induced cross-linking of unmodified proteins (PICUP)
ThT assay
MTT assay
Transmission Electron Microscopy (TEM)
Ion titration and BisANS fluorescence
Metal reduction assay
1.3 Result………………………………………………… 21
Clinical Description and Genetic analysis
D678H Enhances Amyloidogenic Cleavage and Increases the Aβ42/40
D678H Switches the Aβ Aggregation Process
D678H Promotes Aβ42 Neurotoxicity
D678H Alters the Biochemical Features of Ion-induced Aβ Assemblies
D678H Promotes the Interaction of Zn2+ and Cu2+ With Aβ
D678H Has Lower Redox Activity
2.4 Discussion……………………………………… 36
Effect of Intra-Aβ Mutations on APP Processing and Sorting
Role of the Aβ N-terminal Region in Toxicity and Aggregation
Effect of Metal Ions on Aβ Aggregation
Redox Activity of Aβ
2.5 Conclusion………………………………………… 41

Chapter 3. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca2+ Accumulation----------------------42

3.1 Introduction………………………………………… 43
Localization of PS1 mutations
Presenilin and γ-Secretase
PS1 Function Independent of γ-Secretase Activity
Discovery of the PS1 G206D Mutation
3.2 Method………………………………………………………………… 46
Cell Culture
Plasmids
Immunoprecipitation (IP) Analysis
Gel Electrophoresis and Western Blotting Analysis
Cellular Organelle Fractionation
Immunocytochemistry
Enzyme-Linked Immunosorbent Assay (ELISA)
Fura-2-AM Ca2+ Imaging Experiments
Autophagy Assay
Apo-BrdU-RedTM In situ BrdU (TUNEL) labeling assay
Propidium Iodide Staining for Cell Cycle Analysis
Flow Cytometry
3.3 Result………………………………………………………………… 52
G206D Reduces PS1-Pen2 Interaction But Not γ-Secretase Activation
G206D Increases the Production of Aβ42 But Not NICD
G206D Disrupts the ER Ca2+ Homeostasis
G206D Alters PS1 Localization in ER and Early Endosome
G206D Did Not Affect Lysosomal Calcium and Autophagy
G206D Did Not Affect Cell Death Rate Under Oxidative Stress
3.4 Discussion………………………………………………………………… 64
Effects of the G206D mutation on γ-secretase formation and activity
G206D mutation increased ER Ca2+ storage but not lysosomal function
Subcellular distribution of PS1 altered by the G206D mutation
G206D mutation did not alter cell survival under oxidative stress
Calcium dysregulation as a driver for AD pathology
3.5 Conclusion………………………………………………………………… 70

Chapter 4. General Discussion and Conclusion--------- 71

4.1 General Discussion………………………………………………………… 72
Sporadic Alzheimer’s disease
What’s going on in the world
Taiwan Biobank
Implications from our studies
4.2 Conclusion……………………………………………………….………… 78

References------------------------- 80



List of Figures
Chapter 1
Figure 1-1. Challenge of super-aged society and dementia population in Taiwan……………….2
Figure 1-2. APP processing via two alternative pathways…………………………...……………..4
Figure 1-3. Sequential processing of C99 by γ-secretase releases Aβ products………..…………..5
Figure 1-4. Amyloid cascade………………………………………………………………………….11

Chapter 2
Figure 2-1. APP mutations linked to Alzheimer’s disease………………………..………….……..13
Figure 2-2. Aβ self-assembly………………….………………………………………………………14
Figure 2-3. A schematic energy landscape for protein folding and aggregation.…………………14
Figure 2-4. Model of Aβ coordinated to zinc or copper.…………………………………………….15
Figure 2-5. Pedigree and clinical data identify a novel familial Alzheimer’s disease mutation at
Aβ N-terminus……………………………………………………………………………23
Figure 2-6. D678H mutation enhances amyloidogenic pathway and increases extracellular
Aβ42/40 ratio………..……………………………………………………………………25
Figure 2-7. D678H mutation did not alter intracellular Aβ level..…………………………………26
Figure 2-8. Transfect efficiency and APP maturity of APPwt and APPD678H in HEK293T cell….26
Figure 2-9. D678H mutation promotes Aβ40 HMW but Aβ42 LMW assembly formation………28
Figure 2-10. Aβ morphology in the presence or absence of metal ions was revealed by TEM…...29
Figure 2-11. Different Aβ preparations also confirmed that the D678H mutation promotes Aβ40
HMW but Aβ42 LMW assemblies formation.…..…………………………………….30
Figure 2-12. D678H mutation enhances the neurotoxicity of Aβ42…………………………...……31
Figure 2-13. D678H mutation shifts Zn2+ and Cu2+-induced assemblies toward smaller oligomers
with fewer fibrils. ……………..…………..……….……………………………………33
Figure 2-14. D678H mutation promotes the binding of Zn2+ and Cu2+ to Aβ……………………35
Figure 2-15. The representative emission spectra of BisANS………………………………..…..…35
Figure 2-16. D678H mutation decreases the redox activity of Aβ42 in metal reduction assay...36
Figure 2-17. The effect of Aβ-N-terminal mutations on amyloidogenic cleavage…………………37

Chapter 3
Figure 3-1. Presenilin mutations linked to Alzheimer disease……………………………………...43
Figure 3-2. γ-Secretase complex..……………………………………………………………………..44
Figure 3-3. GFP-tagged PS1 variants were endoproteo- lytically processed………………………47
Figure 3-4. G206D mutation reduced PS1-Pen2 interaction but not PS1 endoproteolysis……….53
Figure 3-5. G206D mutation increased Aβ42 ratio but not NICD levels….………………...………55
Figure 3-6. G206D mutation increased ER Ca2+ storage.……………...………………...…………57
Figure 3-7. G206D mutation decreased PS1 levels in ER but increased PS1 levels in early
endosome.….......………………...……...………………...……...………………...…..…59
Figure 3-8. G206D mutation did not alter protein stability………………...……...……….………60
Figure 3-9. G206D mutation did not affect autophagosome maturation and lysosomal Ca2+
storage…….………...……...……….……………...……...……….……………...……..61
Figure 3-10. G206D mutation did not alter survival response under oxidative stress……………63
Figure 3-11. PS1 function independent of γ-secretase…...……………..……...……….…...………66
Figure 3-12. Model of the polar interface in TMD4PS1 and assigned function of polar amino
acids…………….……………..……...……….…...……………..……...……….…...…67

Chapter 4
Figure 4-1. The graph depicts the biomarkers as indicators of Alzheimer’s disease..……..……..74
Figure 4-2. Models of zinc and copper in the glutamatergic synapse in health and Alzheimer’s
disease...……….…...……………..…….......……….…...……………..……...……….…75
Figure 4-3. Role of STIM2-nSOC-CaMKII Pathway in Maintenance of Mushroom Postsynaptic
Spines..…...……….………….…...…………….…...………...……….…...……………..76
Figure 4-4. Schematic representation of PS1FAD mutations analyzed in ER calcium leak function
experiments.….…...…………….…...….…...…………….…...………….…...…………78
 

1. Syme CD, Nadal RC, Rigby SE, Viles JH (2004) Copper binding to the amyloid-beta (Abeta) peptide associated with Alzheimer's disease: folding, coordination geometry, pH dependence, stoichiometry, and affinity of Abeta-(1-28): insights from a range of complementary spectroscopic techniques. J Biol Chem 279 (18):18169-18177. doi:10.1074/jbc.M313572200
2. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 (5580):353-356. doi:10.1126/science.1072994
3. Jahn TR, Radford SE (2005) The Yin and Yang of protein folding. Febs J 272 (23):5962-5970. doi:10.1111/j.1742-4658.2005.05021.x
4. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362 (4):329-344. doi:10.1056/NEJMra0909142
5. Roychaudhuri R, Yang M, Hoshi MM, Teplow DB (2009) Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem 284 (8):4749-4753. doi:10.1074/jbc.R800036200
6. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3 (3):186-191. doi:10.1016/j.jalz.2007.04.381
7. Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex 4 (2):138-150
8. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer's disease. Lancet 368 (9533):387-403. doi:10.1016/S0140-6736(06)69113-7
9. Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA, Posner SF, Viitanen M, Winblad B, Ahlbom A (1997) Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci 52 (2):M117-125
10. Chouraki V, Seshadri S (2014) Genetics of Alzheimer's disease. Adv Genet 87:245-294. doi:10.1016/B978-0-12-800149-3.00005-6
11. Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M (1999) No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 90 (4):1207-1216
12. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96 (21):11872-11877
13. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89 (4):629-639
14. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387 (6630):288-292. doi:10.1038/387288a0
15. Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B (2012) The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. Embo J 31 (10):2261-2274. doi:10.1038/emboj.2012.79
16. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y (2009) gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 29 (41):13042-13052. doi:10.1523/JNEUROSCI.2362-09.2009
17. Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC, Ihara Y (2004) Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry 43 (42):13532-13540. doi:10.1021/bi049399k
18. Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B (2010) Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. Embo J 29 (19):3408-3420. doi:10.1038/emboj.2010.211
19. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 370 (4):311-321. doi:10.1056/NEJMoa1312889
20. Lannfelt L, Relkin NR, Siemers ER (2014) Amyloid-ss-directed immunotherapy for Alzheimer's disease. J Intern Med 275 (3):284-295. doi:10.1111/joim.12168
21. De Strooper B, Gutierrez LC (2014) Learning by Failing: Ideas and Concepts to Tackle gamma-Secretases in Alzheimer Disease and Beyond. Annu Rev Pharmacol Toxicol. doi:10.1146/annurev-pharmtox-010814-124309
22. Yan R, Vassar R (2014) Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13 (3):319-329. doi:10.1016/S1474-4422(13)70276-X
23. Felsenstein KM, Hunihan LW, Roberts SB (1994) Altered cleavage and secretion of a recombinant beta-APP bearing the Swedish familial Alzheimer's disease mutation. Nat Genet 6 (3):251-255. doi:10.1038/ng0394-251
24. Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Jr., Eckman C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264 (5163):1336-1340
25. Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49 (6):697-705
26. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci 4 (9):887-893. doi:10.1038/nn0901-887
27. Hori Y, Hashimoto T, Wakutani Y, Urakami K, Nakashima K, Condron MM, Tsubuki S, Saido TC, Teplow DB, Iwatsubo T (2007) The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation. J Biol Chem 282 (7):4916-4923. doi:10.1074/jbc.M608220200
28. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8 (2):101-112. doi:10.1038/nrm2101
29. Golde TE, Schneider LS, Koo EH (2011) Anti-abeta therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 69 (2):203-213. doi:10.1016/j.neuron.2011.01.002
30. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci 158 (1):47-52
31. Bush AI (2003) The metallobiology of Alzheimer's disease. Trends Neurosci 26 (4):207-214. doi:10.1016/S0166-2236(03)00067-5
32. Sparks DL, Schreurs BG (2003) Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A 100 (19):11065-11069. doi:10.1073/pnas.1832769100
33. Danielsson J, Pierattelli R, Banci L, Graslund A (2007) High-resolution NMR studies of the zinc-binding site of the Alzheimer's amyloid beta-peptide. Febs J 274 (1):46-59. doi:10.1111/j.1742-4658.2006.05563.x
34. Chen WT, Liao YH, Yu HM, Cheng IH, Chen YR (2011) Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-beta stability, oligomerization, and aggregation: amyloid-beta destabilization promotes annular protofibril formation. J Biol Chem 286 (11):9646-9656. doi:10.1074/jbc.M110.177246
35. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham KJ, Bush AI (2008) Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59 (1):43-55. doi:10.1016/j.neuron.2008.06.018
36. Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg H, Ingelsson M, Masters CL, Tanzi RE, Cummings JL, Herd CM, Bush AI (2010) PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis 20 (2):509-516. doi:10.3233/JAD-2010-1390
37. Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A, Yates J, Cotman C, Glabe C (1992) Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J Biol Chem 267 (1):546-554
38. Jan A, Hartley DM, Lashuel HA (2010) Preparation and characterization of toxic Abeta aggregates for structural and functional studies in Alzheimer's disease research. Nat Protoc 5 (6):1186-1209. doi:10.1038/nprot.2010.72
39. Bitan G, Lomakin A, Teplow DB (2001) Amyloid beta-protein oligomerization: prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J Biol Chem 276 (37):35176-35184. doi:10.1074/jbc.M102223200
40. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI (1999) Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274 (52):37111-37116
41. Glabe CG (2008) Structural Classification of Toxic Amyloid Oligomers. J Biol Chem 283 (44):29639-29643. doi:10.1074/jbc.R800016200
42. Guerreiro RJ, Baquero M, Blesa R, Boada M, Bras JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gomez-Isla T, Hernandez I, Lleo A, Machado A, Martinez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Perez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sanchez-Valle R, Santana I, Tarraga L, Valdivieso F, Singleton A, Hardy J, Clarimon J (2010) Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol of aging 31 (5):725-731
43. Minicozzi V, Stellato F, Comai M, Serra MD, Potrich C, Meyer-Klaucke W, Morante S (2008) Identifying the minimal copper- and zinc-binding site sequence in amyloid-beta peptides. J Biol Chem 283 (16):10784-10792. doi:M707109200 [pii]
10.1074/jbc.M707109200
44. Nair N, Perry G, Smith M, Reddy V (2010) NMR studies of zinc, copper, and iron binding to histidine, the principal metal ion complexing site of amyloid-beta peptide. J Alzheimers Dis 20 (1):57-66
45. LeVine H, 3rd (2002) 4,4(')-Dianilino-1,1(')-binaphthyl-5,5(')-disulfonate: report on non-beta-sheet conformers of Alzheimer's peptide beta(1-40). Arch Biochem Biophys 404 (1):106-115
46. Chen WT, Liao YH, Yu HM, Cheng IH, Chen YR (2011) Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-beta Stability, Oligomerization, and Aggregation. J Biol Chem 286 (11):9646-9656. doi:10.1074/jbc.M110.177246
47. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI (1999) Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Bio Chem 274 (52):37111-37116
48. O'Brien RJ, Wong PC (2011) Amyloid Precursor Protein Processing and Alzheimer's Disease. Annu Rev Neurosci 34 (1):185-204. doi:doi:10.1146/annurev-neuro-061010-113613
49. Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli AR, Prioni S, Erbetta A, Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni C, Francescucci B, Spagnoli A, Cantu L, Del Favero E, Levy E, Salmona M, Tagliavini F (2009) A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis. Science 323 (5920):1473-1477. doi:10.1126/science.1168979
50. Zhou L, Brouwers N, Benilova I, Vandersteen A, Mercken M, Van Laere K, Van Damme P, Demedts D, Van Leuven F, Sleegers K, Broersen K, Van Broeckhoven C, Vandenberghe R, De Strooper B (2011) Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β′-site increases Aβ generation. EMBO Molecular Medicine 3 (5):291-302. doi:10.1002/emmm.201100138
51. De Jonghe C, Zehr C, Yager D, Prada C-M, Younkin S, Hendriks L, Van Broeckhoven C, Eckman C (1998) Flemish and Dutch Mutations in Amyloid [beta] Precursor Protein Have Different Effects on Amyloid [beta] Secretion. . Neurobiology of Disease 5 (4):281-286
52. Lin YC, Wang JY, Wang KC, Liao JY, Cheng IH (2014) Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-beta production. J Neurochem 131 (4):407-412. doi:10.1111/jnc.12829
53. Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Chishti MA, Cox DW, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D (2003) In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A 100 (24):14193-14198. doi:10.1073/pnas.2332851100
54. Acevedo KM, Hung YH, Dalziel AH, Li QX, Laughton K, Wikhe K, Rembach A, Roberts B, Masters CL, Bush AI, Camakaris J (2011) Copper promotes the trafficking of the amyloid precursor protein. J Biol Chem 286 (10):8252-8262. doi:10.1074/jbc.M110.128512
55. Zheng W, Xin N, Chi ZH, Zhao BL, Zhang J, Li JY, Wang ZY (2009) Divalent metal transporter 1 is involved in amyloid precursor protein processing and Abeta generation. FASEB 23 (12):4207-4217. doi:10.1096/fj.09-135749
56. Wang CY, Wang T, Zheng W, Zhao BL, Danscher G, Chen YH, Wang ZY (2010) Zinc overload enhances APP cleavage and Abeta deposition in the Alzheimer mouse brain. PloS one 5 (12):e15349. doi:10.1371/journal.pone.0015349
57. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142 (6):857-867. doi:10.1016/j.cell.2010.08.014
58. Dahms SO, Konnig I, Roeser D, Guhrs KH, Mayer MC, Kaden D, Multhaup G, Than ME (2012) Metal Binding Dictates Conformation and Function of the Amyloid Precursor Protein (APP) E2 Domain. J Mol Biol 416 (3):438-452. doi:10.1016/j.jmb.2011.12.057
59. Schmidt M, Sachse C, Richter W, Xu C, Fandrich M, Grigorieff N (2009) Comparison of Alzheimer Abeta(1-40) and Abeta(1-42) amyloid fibrils reveals similar protofilament structures. . Proc Natl Acad Sci USA 106 (47):19813-19818
60. Olofsson A, Lindhagen-Persson M, Sauer-Eriksson AE, Ohman A (2007) Amide solvent protection analysis demonstrates that amyloid-beta(1-40) and amyloid-beta(1-42) form different fibrillar structures under identical conditions. Biochem J 404 (1):63-70. doi:BJ20061561 [pii]
10.1042/BJ20061561
61. Duce JA, Bush AI (2010) Biological metals and Alzheimer's disease: Implications for therapeutics and diagnostics. Prog Neurobiol 92 (1):1-18
62. Faux N, Ritchie C, Gunn A, Rembach A, Tsatsanis A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg H, Ingelsson M, Masters C, Tanzi R, Cummings J, Herd C, Bush A (2010) PBT2 Rapidly Improves Cognition in Alzheimer's Disease: Additional Phase II Analyses J Alzheimers Dis 20 (2):509-516
63. Dai X, Sun Y, Gao Z, Jiang Z (2010) Copper Enhances Amyloid-β Peptide Neurotoxicity and non β-Aggregation: A Series of Experiments Conducted upon Copper-Bound and Copper-Free Amyloid-β Peptide. J Mol Neurosci 41 (1):66-73. doi:10.1007/s12031-009-9282-8
64. Shin BK, Saxena S (2011) Substantial contribution of the two imidazole rings of the His13-His14 dyad to Cu(II) binding in amyloid-beta(1-16) at physiological pH and its significance. J Physi Chemi A 115 (34):9590-9602. doi:10.1021/jp200379m
65. Karr JW, Akintoye H, Kaupp LJ, Szalai VA (2005) N-Terminal deletions modify the Cu2+ binding site in amyloid-beta. Biochemistry 44 (14):5478-5487. doi:10.1021/bi047611e
66. Bush AI, Pettingell WH, Multhaup G, Paradis Md, Vonsattel J-P, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994) Rapid Induction of Alzheimer Abeta Amyloid Formation by Zinc. Science 265 (5177):1464-1467
67. Miller Y, Ma B, Nussinov R (2010) Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states. Proc Natl Acad Sci U S A 107 (21):9490-9495. doi:0913114107 [pii]
10.1073/pnas.0913114107
68. Clements A, Allsop D, Walsh DM (1996) Aggregation and Metal-Binding Properties of Mutant Forms of the Amyloid Beta Peptide of Alzheimer's Disease. J Neurochem 66 (2):740-747
69. Nakamura M, Shishido N, Nunomura A, Smith MA, Perry G, Hayashi Y, Nakayama K, Hayashi T (2007) Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron. Biochemistry 46 (44):12737-12743. doi:10.1021/bi701079z
70. Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer's disease amyloid [beta] peptide. Biochim Biophys Acta 1768 (8):1976-1990
71. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C, Beyreuther K, Carrington D, Masters CL, Cherny RA, Cappai R, Bush AI (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid. FASEB J 18 (12):1427-1429. doi:10.1096/fj.04-1890fje
04-1890fje [pii]
72. Smith DP, Ciccotosto GD, Tew DJ, Fodero-Tavoletti MT, Johanssen T, Masters CL, Barnham KJ, Cappai R (2007) Concentration Dependent Cu2+ Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-beta Peptide. Biochemistry 46 (10):2881-2891. doi:10.1021/bi0620961
73. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, Huang X, Moir RD, Wang D, Sayre LM, Smith MA, Chen SG, Bush AI (2004) Copper mediates dityrosine cross-linking of Alzheimer's amyloid-beta. Biochemistry 43 (2):560-568. doi:10.1021/bi0358824
74. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41 (10):1088-1093. doi:10.1038/ng.440
75. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39 (2):168-177. doi:10.1038/ng1943
76. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, Green RC, Rogaeva E, St George-Hyslop P, Arnold SE, Barber R, Beach T, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Cummings JL, DeCarli C, DeKosky ST, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman AP, Lopez OL, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Parisi JE, Perl DP, Peskind E, Petersen RC, Poon WW, Quinn JF, Rajbhandary RA, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Cantwell LB, Dombroski BA, Beekly D, Lunetta KL, Martin ER, Kamboh MI, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43 (5):436-441. doi:10.1038/ng.801
77. Bezprozvanny I (2013) Presenilins and calcium signaling-systems biology to the rescue. Sci Signal 6 (283):pe24. doi:10.1126/scisignal.2004296
78. Hardy J (2007) Putting presenilins centre stage. Introduction to the Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8 (2):134-135. doi:10.1038/sj.embor.7400899
79. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of g-secretase activity. Nat Cell Biol 5 (5):486–488. doi:10.1038/ncb960
80. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature 422 (6930):438-441. doi:10.1038/nature01506
81. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398 (6727):518-522. doi:10.1038/19083
82. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390. doi:10.1038/34910
83. Rechards M, Xia W, Oorschot VM, Selkoe DJ, Klumperman J (2003) Presenilin-1 exists in both pre- and post-Golgi compartments and recycles via COPI-coated membranes. Traffic 4 (8):553-565. doi:10.1034/j.1600-0854.2003.t01-1-00114.x
84. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2 (5):a006270. doi:10.1101/cshperspect.a006270
85. Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, De Strooper B, Annaert W (2001) The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J Cell Biol 154 (4):731-740. doi:10.1083/jcb.200104045
86. Fassler M, Zocher M, Klare S, de la Fuente AG, Scheuermann J, Capell A, Haass C, Valkova C, Veerappan A, Schneider D, Kaether C (2010) Masking of transmembrane-based retention signals controls ER export of gamma-secretase. Traffic 11 (2):250-258. doi:10.1111/j.1600-0854.2009.01014.x
87. Kim SH, Sisodia SS (2005) Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 280 (51):41953-41966. doi:10.1074/jbc.M509070200
88. Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T (2005) Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 280 (51):41967-41975. doi:10.1074/jbc.M509066200
89. Fassler M, Li X, Kaether C (2011) Polar transmembrane-based amino acids in presenilin 1 are involved in endoplasmic reticulum localization, Pen2 protein binding, and gamma-secretase complex stabilization. J Biol Chem 286 (44):38390-38396. doi:10.1074/jbc.M111.252429
90. Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G (2002) A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41 (8):2825-2835. doi:10.1021/bi015794o
91. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, Teplow DB, Haass C (2001) Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2 (9):835-841. doi:10.1093/embo-reports/kve180
92. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89:629–639. doi:10.1016/S0092-8674(00)80244-5
93. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387:288–292. doi:10.1038/387288a0
94. Shen J, Kelleher RJ, 3rd (2007) The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A 104 (2):403-409. doi:10.1073/pnas.0608332104
95. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee S-F, Hao Y-H, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126 (5):981–993. doi:10.1016/j.cell.2006.06.059
96. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141 (7):1146-1158. doi:10.1016/j.cell.2010.05.008
97. Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP (2000) Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275 (24):18195–18200. doi:10.1074/jbc.m000040200
98. Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24 (2):508–513. doi:10.1523/JNEUROSCI.4386-03.2004
99. Bandara S, Malmersjo S, Meyer T (2013) Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA. Sci Signal 6 (283):ra56. doi:10.1126/scisignal.2003649
100. Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ, Feske S, White CL, 3rd, Bezprozvanny I (2014) Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 82 (1):79-93. doi:10.1016/j.neuron.2014.02.019
101. Schneider I, Reversé D, Dewachter I, Ris L, Caluwaerts N, Kuipéri C, Gilis M, Geerts H, Kretzschmar H, Godaux E, Moechars D, Van Leuven F, Herms J (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544. doi:10.1074/jbc.M010977200
102. Goussakov I, Miller MB, Stutzmann GE (2010) NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice. J Neurosci 30 (36):12128-12137. doi:10.1523/JNEUROSCI.2474-10.2010
103. Wu B, Yamaguchi H, Lai FA, Shen J (2013) Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc Natl Acad Sci USA 110 (37):15091-15096. doi:10.1073/pnas.1304171110
104. Neely KM, Green KN, LaFerla FM (2011) Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a gamma-secretase-independent manner. J Neurosci 31 (8):2781-2791. doi:10.1523/JNEUROSCI.5156-10.2010
105. Luzio JP, Bright NA, Pryor PR (2007) The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Biochem Soc Trans 35 (Pt 5):1088-1091. doi:10.1042/BST0351088
106. Saftig P, Klumperman J (2009) Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10 (9):623-635. doi:10.1038/nrm2745
107. Bezprozvanny I (2012) Presenilins: a novel link between intracellular calcium signaling and lysosomal function? J Cell Biol 198 (1):7-10. doi:10.1083/jcb.201206003
108. Coen K, Flannagan RS, Baron S, Carraro-Lacroix LR, Wang D, Vermeire W, Michiels C, Munck S, Baert V, Sugita S, Wuytack F, Hiesinger PR, Grinstein S, Annaert W (2012) Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol 198 (1):23-35. doi:10.1083/jcb.201201076
109. Neely Kayala KM, Dickinson GD, Minassian A, Walls KC, Green KN, Laferla FM (2012) Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: implications for lysosomal function. Brain Res 1489:8-16. doi:10.1016/j.brainres.2012.10.036
110. Baki L, Neve RL, Shao Z, Shioi J, Georgakopoulos A, Robakis NK (2008) Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling. J Neurosci 28 (2):483-490. doi:10.1523/jneurosci.4067-07.2008
111. Wu Y-Y, Cheng IH-J, Lee C-C, Chiu M-J, Lee M-J, Chen T-F, Hsu J-L (2011) Clinical Phenotype of G206D Mutation in the Presenilin 1 Gene in Pathologically Confirmed Familial Alzheimer's Disease. J Alzheimer's Dis 25 (1):145-150. doi:10.3233/JAD-2011-102031.
112. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D (2005) Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update. J Med Genet 42 (10):793-795. doi:10.1136/jmg.2005.033456
113. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R (2001) A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. Jama 286 (18):2257-2263. doi:10.1001/jama.286.18.2257.
114. Park HK, Na DL, Lee JH, Kim JW, Ki CS (2008) Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci 23 (2):213-217. doi:10.3346/jkms.2008.23.2.213
115. Goldman JS, Reed B, Gearhart R, Kramer JH, Miller BL (2002) Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry 17 (7):649-651. doi:10.1002/gps.657
116. Kim SD, Kim J (2008) Sequence analyses of presenilin mutations linked to familial Alzheimer's disease. Cell Stress Chaperones 13 (4):401-412. doi:10.1007/s12192-008-0046-0
117. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci USA 96 (21):11872-11877. doi:10.1073/pnas.96.21.11872
118. Kuo LH, Hu MK, Hsu WM, Tung YT, Wang BJ, Tsai WW, Yen CT, Liao YF (2008) Tumor necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin. Mol Biol Cell 19 (10):4201-4212. doi:10.1091/mbc.E07-09-0987
119. Tung YT, Wang BJ, Hsu WM, Hu MK, Her GM, Huang WP, Liao YF (2014) Presenilin-1 regulates the expression of p62 to Govern p62-dependent Tau degradation. Mol Neurobiol 49 (1):10-27. doi:10.1007/s12035-013-8482-y
120. Tung YT, Hsu WM, Lee H, Huang WP, Liao YF (2010) The evolutionarily conserved interaction between LC3 and p62 selectively mediates autophagy-dependent degradation of mutant huntingtin. Cell Mol Neurobiol 30 (5):795-806. doi:10.1007/s10571-010-9507-y
121. Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell 16 (2):927-942. doi:10.1091/mbc.E04-07-0614
122. Tseng LC, Chen RH (2011) Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor. Mol Biol Cell 22 (18):3306-3317. doi:10.1091/mbc.E11-03-0199
123. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260 (6):3440-3450
124. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3 (5):452-460
125. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1 (3):1458-1461. doi:10.1038/nprot.2006.238
126. Dean PN, Jett JH (1974) Mathematical analysis of DNA distributions derived from flow microfluorometry. J Cell Biol 60 (2):523-527. doi:10.1083/jcb.60.2.523
127. Chen F, Gu Y, Hasegawa H, Ruan X, Arawaka S, Fraser P, Westaway D, Mount H, St George-Hyslop P (2002) Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch. J Biol Chem 277 (39):36521-36526. doi:10.1074/jbc.M205093200
128. Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H (2002) Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci USA 99 (12):8025-8030. doi:10.1073/pnas.112686799
129. Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393 (6683):382-386. doi:10.1038/30756
130. Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Bio Cell 16 (2):927-942. doi:10.1091/mbc.E04-07-0614
131. Shilling D, Mak DO, Kang DE, Foskett JK (2012) Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. J Biol Chem 287 (14):10933-10944. doi:10.1074/jbc.M111.300491
132. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM (2008) SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production. J Cell Biol 181 (7):1107-1116. doi:10.1083/jcb.200706171
133. Kalies KU, Rapoport TA, Hartmann E (1998) The beta subunit of the Sec61 complex facilitates cotranslational protein transport and interacts with the signal peptidase during translocation. J Cell Biol 141 (4):887-894. doi:10.1083/jcb.141.4.887
134. Petanceska SS, Seeger M, Checler F, Gandy S (2000) Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway. J Neurochem 74 (5):1878-1884. doi:10.1046/j.1471-4159.2000.0741878.x
135. Gorvel JP, Chavrier P, Zerial M, Gruenberg J (1991) rab5 controls early endosome fusion in vitro. Cell 64 (5):915-925. doi:10.1016/0092-8674(91)90316-q.
136. Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA (2006) Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease. J Neurochem 96 (5):1322-1335. doi:10.1111/j.1471-4159.2005.03647.x
137. Nakajima M, Miura M, Aosaki T, Shirasawa T (2001) Deficiency of presenilin-1 increases calcium-dependent vulnerability of neurons to oxidative stress in vitro. J Neurochem 78 (4):807-814. doi:10.1046/j.1471-4159.2001.00478.x
138. Lizard G, Miguet C, Gueldry S, Monier S, Gambert P (1997) [Flow cytometry measurement of DNA fragmentation in the course of cell death via apoptosis. New techniques for evaluation of DNA status for the pathologist]. Ann Pathol 17 (1):61-66. doi:AP-03-1997-17-1-0242-6498-101019-ART85
139. Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C (2004) The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J 23 (24):4738-4748. doi:10.1038/sj.emboj.7600478
140. Kaether C, Scheuermann J, Fassler M, Zilow S, Shirotani K, Valkova C, Novak B, Kacmar S, Steiner H, Haass C (2007) Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1. EMBO Rep 8 (8):743-748. doi:10.1038/sj.embor.7401027
141. Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, Serneels L, Fullekrug J, Annaert W (2007) Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway. J Cell Biol 176 (5):629-640. doi:10.1083/jcb.200609180
142. Berezovska O, Lleo A, Herl LD, Frosch MP, Stern EA, Bacskai BJ, Hyman BT (2005) Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci 25 (11):3009-3017. doi:10.1523/JNEUROSCI.0364-05.2005
143. Chau DM, Crump CJ, Villa JC, Scheinberg DA, Li YM (2012) Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of gamma-secretase. J Biol Chem 287 (21):17288-17296. doi:10.1074/jbc.M111.300483
144. Isoo N, Sato C, Miyashita H, Shinohara M, Takasugi N, Morohashi Y, Tsuji S, Tomita T, Iwatsubo T (2007) Abeta42 overproduction associated with structural changes in the catalytic pore of gamma-secretase: common effects of Pen-2 N-terminal elongation and fenofibrate. J Biol Chem 282 (17):12388-12396. doi:10.1074/jbc.M611549200
145. Querfurth HW, Selkoe DJ (1994) Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33 (15):4550-4561. doi:10.1021/bi00181a016.
146. Schultz ML, Tecedor L, Chang M, Davidson BL (2011) Clarifying lysosomal storage diseases. Trends Neurosci 34 (8):401-410. doi:10.1016/j.tins.2011.05.006
147. McBrayer M, Nixon RA (2013) Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime. Biochem Soc Trans 41 (6):1495-1502. doi:10.1042/BST20130201
148. Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K, Sisodia SS (2012) A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J Neurosci 32 (25):8633-8648. doi:10.1523/JNEUROSCI.0556-12.2012
149. Frykman S, Hur JY, Franberg J, Aoki M, Winblad B, Nahalkova J, Behbahani H, Tjernberg LO (2010) Synaptic and endosomal localization of active gamma-secretase in rat brain. PLoS One 5 (1):e8948. doi:10.1371/journal.pone.0008948
150. Bonifacino JS, Cosson P, Shah N, Klausner RD (1991) Role of potentially charged transmembrane residues in targeting proteins for retention and degradation within the endoplasmic reticulum. Embo J 10 (10):2783-2793
151. Siman R, Flood DG, Thinakaran G, Neumar RW (2001) Endoplasmic reticulum stress-induced cysteine protease activation in cortical neurons: effect of an Alzheimer's disease-linked presenilin-1 knock-in mutation. J Biol Chem 276 (48):44736-44743. doi:10.1074/jbc.M104092200
152. Liang G, Wang Q, Li Y, Kang B, Eckenhoff MF, Eckenhoff RG, Wei H (2008) A presenilin-1 mutation renders neurons vulnerable to isoflurane toxicity. Anesth Analg 106 (2):492-500, table of contents. doi:10.1213/ane.0b013e3181605b71
153. Janicki SM, Stabler SM, Monteiro MJ (2000) Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging 21 (6):829-836. doi:10.1016/S0197-4580(00)00222-0
154. Janicki SM, Monteiro MJ (1999) Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest potentiated by the Alzheimer's disease PS2(N141I)mutant. Am J Pathol 155 (1):135-144. doi:10.1016/S0002-9440(10)65108-5
155. Johnston LA, Edgar BA (1998) Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394 (6688):82-84. doi:10.1038/27925
156. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y (2013) Structure of a presenilin family intramembrane aspartate protease. Nature 493 (7430):56-61. doi:10.1038/nature11801
157. Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM, Rabinovici GD, Jagust WJ (2013) Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 70 (12):1512-1519. doi:10.1001/jamaneurol.2013.4013
158. Jack CR, Jr., Wiste HJ, Weigand SD, Knopman DS, Lowe V, Vemuri P, Mielke MM, Jones DT, Senjem ML, Gunter JL, Gregg BE, Pankratz VS, Petersen RC (2013) Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology 81 (20):1732-1740. doi:10.1212/01.wnl.0000435556.21319.e4
159. Larson EB, Yaffe K, Langa KM (2013) New insights into the dementia epidemic. N Engl J Med 369 (24):2275-2277. doi:10.1056/NEJMp1311405
160. Ngandu T, Lehtisalo J, Levalahti E, Laatikainen T, Lindstrom J, Peltonen M, Solomon A, Ahtiluoto S, Antikainen R, Hanninen T, Jula A, Mangialasche F, Paajanen T, Pajala S, Rauramaa R, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M (2014) Recruitment and baseline characteristics of participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)-a randomized controlled lifestyle trial. Int J Environ Res Public Health 11 (9):9345-9360. doi:10.3390/ijerph110909345
161. Duce JA, Bush AI (2010) Biological metals and Alzheimer's disease: implications for therapeutics and diagnostics. Prog Neurobiol 92 (1):1-18. doi:10.1016/j.pneurobio.2010.04.003
162. Soboloff J, Rothberg BS, Madesh M, Gill DL (2012) STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13 (9):549-565. doi:10.1038/nrm3414