Assembly, Maturation, and Trafficking of the Gamma-secretase Complex in Alzheimer's Disease

Overview

Journal Curr Alzheimer Res

Publisher Bentham Science Publishers

Specialty Neurology

Date 2008 Apr 9

PMID 18393798

Citations 57

Authors

Daniel R Dries

Gang Yu

Affiliations

Soon will be listed here.

Abstract

In this review, we discuss the biology of gamma-secretase, an enigmatic enzyme complex that is responsible for the generation of the amyloid-beta peptide that constitutes the amyloid plaques of Alzheimer's disease. We begin with a brief review on the processing of the amyloid precursor protein and a brief discussion on the family of enzymes involved in regulated intramembrane proteolysis, of which gamma-secretase is a member. We then identify the four major components of the gamma-secretase complex - presenilin, nicastrin, Aph-1, and Pen-2 - with a focus on the identification of each and the role that each plays in the maturation and activity of the complex. We also discuss two new proteins that may play a role in modulating the assembly and activity of the gamma-secretase complex. Next, we summarize the known subcellular locations of each gamma-secretase component and the sites of gamma-secretase activity, as defined by the production of Abeta. Finally, we close by synthesizing all of the included topics into an overarching model for the assembly and trafficking of the gamma-secretase complex, which serves as a launching point for further questions into the biology and function of gamma-secretase in Alzheimer's disease.

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References

Shiraishi H, Sai X, Wang H, Maeda Y, Kurono Y, Nishimura M . PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. J Neurochem. 2004; 90(6):1402-13. DOI: 10.1111/j.1471-4159.2004.02597.x. View

Goutte C, Hepler W, Mickey K, Priess J . aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development. 2000; 127(11):2481-92. DOI: 10.1242/dev.127.11.2481. View

Lichtenthaler S . Ectodomain shedding of the amyloid precursor protein: cellular control mechanisms and novel modifiers. Neurodegener Dis. 2006; 3(4-5):262-9. DOI: 10.1159/000095265. View

Ratovitski T, Slunt H, Thinakaran G, Price D, Sisodia S, Borchelt D . Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem. 1997; 272(39):24536-41. DOI: 10.1074/jbc.272.39.24536. View

Hu Y, Ye Y, Fortini M . Nicastrin is required for gamma-secretase cleavage of the Drosophila Notch receptor. Dev Cell. 2002; 2(1):69-78. DOI: 10.1016/s1534-5807(01)00105-8. View

Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C . Gamma-secretase activity is associated with a conformational change of nicastrin. J Biol Chem. 2003; 278(19):16474-7. DOI: 10.1074/jbc.C300095200. View

Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A . Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000; 407(6800):48-54. DOI: 10.1038/35024009. View

Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman M . Gamma-secretase complex assembly within the early secretory pathway. J Biol Chem. 2004; 280(8):6471-8. DOI: 10.1074/jbc.M409106200. View

Li Y, Lai M, Xu M, Huang Q, Sardana M, Shi X . Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci U S A. 2000; 97(11):6138-43. PMC: 18571. DOI: 10.1073/pnas.110126897. View

10.

Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L . 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. 1999; 96(21):11872-7. PMC: 18379. DOI: 10.1073/pnas.96.21.11872. View

11.

Arawaka S, Hasegawa H, Tandon A, Janus C, Chen F, Yu G . The levels of mature glycosylated nicastrin are regulated and correlate with gamma-secretase processing of amyloid beta-precursor protein. J Neurochem. 2002; 83(5):1065-71. DOI: 10.1046/j.1471-4159.2002.01207.x. View

12.

Kimberly W, LaVoie M, Ostaszewski B, Ye W, Wolfe M, Selkoe D . Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation. J Biol Chem. 2002; 277(38):35113-7. DOI: 10.1074/jbc.M204446200. View

13.

Vetrivel K, Zhang Y, Xu H, Thinakaran G . Pathological and physiological functions of presenilins. Mol Neurodegener. 2006; 1:4. PMC: 1513131. DOI: 10.1186/1750-1326-1-4. View

14.

Tolia A, Chavez-Gutierrez L, De Strooper B . Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J Biol Chem. 2006; 281(37):27633-42. DOI: 10.1074/jbc.M604997200. View

15.

Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, Serneels L . Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway. J Cell Biol. 2007; 176(5):629-40. PMC: 2064021. DOI: 10.1083/jcb.200609180. View

16.

Wang R, Sweeney D, Gandy S, Sisodia S . The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry. J Biol Chem. 1996; 271(50):31894-902. DOI: 10.1074/jbc.271.50.31894. View

17.

Edbauer D, Winkler E, Regula J, Pesold B, Steiner H, Haass C . Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003; 5(5):486-8. DOI: 10.1038/ncb960. View

18.

Borchelt D, Thinakaran G, Eckman C, Lee M, Davenport F, Ratovitsky T . Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996; 17(5):1005-13. DOI: 10.1016/s0896-6273(00)80230-5. View

19.

Lai M, Chen E, Crouthamel M, DiMuzio-Mower J, Xu M, Huang Q . Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem. 2003; 278(25):22475-81. DOI: 10.1074/jbc.M300974200. View

20.

Niimura M, Isoo N, Takasugi N, Tsuruoka M, Ui-Tei K, Saigo K . Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J Biol Chem. 2005; 280(13):12967-75. DOI: 10.1074/jbc.M409829200. View