Chức năng sinh học của Presenilin và vai trò của nó trong quá trình phát sinh bệnh Alzheimer

Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC: Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 1987, 235: 877-880. 10.1126/science.3810169 Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325: 733-736. 10.1038/325733a0 Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM: Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A 1987, 84: 4190-4194. 10.1073/pnas.84.12.4190 St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, et al.: The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 1987, 235: 885-890. 10.1126/science.2880399 Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL: Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 1987, 235: 880-884. 10.1126/science.2949367 Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al.: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991, 349: 704-706. 10.1038/349704a0 Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, et al.: Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science 1992, 258: 668-671. 10.1126/science.1411576 St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, Foncin JF, Montesi M, Bruni A, Sorbi S, et al.: Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nat Genet 1992, 2: 330-334. 10.1038/ng1292-330 Li J, Ma J, Potter H: Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3. Proc Natl Acad Sci U S A 1995, 92: 12180-12184. 10.1073/pnas.92.26.12180 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995, 375: 754-760. 10.1038/375754a0 Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al.: Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995, 269: 973-977. 10.1126/science.7638622 Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD: A familial Alzheimer’s disease locus on chromosome 1. Science 1995, 269: 970-973. 10.1126/science.7638621 Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.: Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 1995, 376: 775-778. 10.1038/376775a0 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993, 261: 921-923. 10.1126/science.8346443 Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993, 90: 1977-1981. 10.1073/pnas.90.5.1977 Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120: 885-890. 10.1016/S0006-291X(84)80190-4 Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y: Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994, 13: 45-53. 10.1016/0896-6273(94)90458-8 Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM: Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986, 261: 6084-6089. Kosik KS, Joachim CL, Selkoe DJ: Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 1986, 83: 4044-4048. 10.1073/pnas.83.11.4044 Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A: Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 1988, 85: 4051-4055. 10.1073/pnas.85.11.4051 Iqbal K, Grundke-Iqbal I, Smith AJ, George L, Tung YC, Zaidi T: Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci U S A 1989, 86: 5646-5650. 10.1073/pnas.86.14.5646 Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, et al.: Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998, 393: 702-705. 10.1038/31508 Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005, 8: 79-84. 10.1038/nn1372 Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440: 352-357. 10.1038/nature04533 Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L: Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 2007, 282: 23818-23828. 10.1074/jbc.M701078200 Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27: 2866-2875. 10.1523/JNEUROSCI.4970-06.2007 Selkoe DJ: Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 2008, 192: 106-113. 10.1016/j.bbr.2008.02.016 Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008, 14: 837-842. 10.1038/nm1782 Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H: A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 2010, 30: 4845-4856. 10.1523/JNEUROSCI.5825-09.2010 Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297: 353-356. 10.1126/science.1072994 Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ: Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990, 248: 1122-1124. 10.1126/science.2111583 Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999, 14: 419-427. 10.1006/mcne.1999.0811 Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999, 402: 537-540. 10.1038/990114 Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286: 735-741. 10.1126/science.286.5440.735 Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999, 402: 533-537. 10.1038/990107 Li Y, Zhou W, Tong Y, He G, Song W: Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription. FASEB J 2006, 20: 285-292. 10.1096/fj.05-4986com Brown MS, Ye J, Rawson RB, Goldstein JL: Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000, 100: 391-398. 10.1016/S0092-8674(00)80675-3 De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998, 391: 387-390. 10.1038/34910 Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000, 407: 48-54. 10.1038/35024009 Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA: Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2000, 2: 463-465. 10.1038/35017108 Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D: aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002, 3: 85-97. 10.1016/S1534-5807(02)00189-2 Goutte C, Tsunozaki M, Hale VA, Priess JR: APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002, 99: 775-779. 10.1073/pnas.022523499 Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C: Reconstitution of gamma-secretase activity. Nat Cell Biol 2003, 5: 486-488. 10.1038/ncb960 Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ: Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 2003, 100: 6382-6387. 10.1073/pnas.1037392100 Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T: The role of presenilin cofactors in the gamma-secretase complex. Nature 2003, 422: 438-441. 10.1038/nature01506 Lee MK, Slunt HH, Martin LJ, Thinakaran G, Kim G, Gandy SE, Seeger M, Koo E, Price DL, Sisodia SS: Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. J Neurosci 1996, 16: 7513-7525. Levitan D, Greenwald I: Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 1995, 377: 351-354. 10.1038/377351a0 Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B, Lendahl U, von Heijne G, Naslund J: A nine-transmembrane domain topology for presenilin 1. J Biol Chem 2005, 280: 35352-35360. 10.1074/jbc.M507217200 Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W: Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J Biol Chem 2006, 281: 26569-26577. 10.1074/jbc.M600592200 Walter J, Capell A, Grunberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB, Fraser P, Hyslop PS, Selkoe DJ, Haass C: The Alzheimer’s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med 1996, 2: 673-691. Culvenor JG, Maher F, Evin G, Malchiodi-Albedi F, Cappai R, Underwood JR, Davis JB, Karran EH, Roberts GW, Beyreuther K, Masters CL: Alzheimer’s disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment. J Neurosci Res 1997, 49: 719-731. 10.1002/(SICI)1097-4547(19970915)49:6<719::AID-JNR6>3.0.CO;2-A Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, Westaway D, George-Hyslop PS, Cordell B, Fraser P, De Strooper B: Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons. J Cell Biol 1999, 147: 277-294. 10.1083/jcb.147.2.277 Kim SH, Lah JJ, Thinakaran G, Levey A, Sisodia SS: Subcellular localization of presenilins: association with a unique membrane pool in cultured cells. Neurobiol Dis 2000, 7: 99-117. 10.1006/nbdi.1999.0280 Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996, 17: 181-190. 10.1016/S0896-6273(00)80291-3 Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P, Teplow DB, Selkoe DJ: Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 1997, 3: 325-337. 10.1006/nbdi.1997.0129 Shirotani K, Takahashi K, Ozawa K, Kunishita T, Tabira T: Determination of a cleavage site of presenilin 2 protein in stably transfected SH-SY5Y human neuroblastoma cell lines. Biochem Biophys Res Commun 1997, 240: 728-731. 10.1006/bbrc.1997.7730 Jacobsen H, Reinhardt D, Brockhaus M, Bur D, Kocyba C, Kurt H, Grim MG, Baumeister R, Loetscher H: The influence of endoproteolytic processing of familial Alzheimer’s disease presenilin 2 on abeta42 amyloid peptide formation. J Biol Chem 1999, 274: 35233-35239. 10.1074/jbc.274.49.35233 Campbell WA, Reed ML, Strahle J, Wolfe MS, Xia W: Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from gamma-secretase. J Neurochem 2003, 85: 1563-1574. 10.1046/j.1471-4159.2003.01799.x Nyabi O, Bentahir M, Horre K, Herreman A, Gottardi-Littell N, Van Broeckhoven C, Merchiers P, Spittaels K, Annaert W, De Strooper B: Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin. J Biol Chem 2003, 278: 43430-43436. 10.1074/jbc.M306957200 Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999, 398: 513-517. 10.1038/19077 Xia W: Relationship between presenilinase and gamma-secretase. Drug News Perspect 2003, 16: 69-74. 10.1358/dnp.2003.16.2.740248 Xia W: From presenilinase to gamma-secretase, cleave to capacitate. Curr Alzheimer Res 2008, 5: 172-178. 10.2174/156720508783954712 Ahn K, Shelton CC, Tian Y, Zhang X, Gilchrist ML, Sisodia SS, Li YM: Activation and intrinsic gamma-secretase activity of presenilin 1. Proc Natl Acad Sci U S A 2010, 107: 21435-21440. 10.1073/pnas.1013246107 Fukumori A, Fluhrer R, Steiner H, Haass C: Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. J Neurosci 2010, 30: 7853-7862. 10.1523/JNEUROSCI.1443-10.2010 Knappenberger KS, Tian G, Ye X, Sobotka-Briner C, Ghanekar SV, Greenberg BD, Scott CW: Mechanism of gamma-secretase cleavage activation: is gamma-secretase regulated through autoinhibition involving the presenilin-1 exon 9 loop? Biochemistry 2004, 43: 6208-6218. 10.1021/bi036072v Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R, Haass C: The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 1999, 274: 7615-7618. 10.1074/jbc.274.12.7615 Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996, 2: 864-870. 10.1038/nm0896-864 Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B: Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2000, 2: 461-462. 10.1038/35017105 Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H: PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 2003, 278: 7850-7854. 10.1074/jbc.C200648200 Zhao G, Liu Z, Ilagan MX, Kopan R: Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci 2010, 30: 1648-1656. 10.1523/JNEUROSCI.3826-09.2010 Ahn CK, Woo SH, Park JM: Surface solubilization of phenanthrene by surfactant sorbed on soils with different organic matter contents. J Hazard Mater 2010, 177: 799-806. 10.1016/j.jhazmat.2009.12.104 Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H: Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 2004, 279: 41340-41345. 10.1074/jbc.M405768200 Shirotani K, Tomioka M, Kremmer E, Haass C, Steiner H: Pathological activity of familial Alzheimer’s disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. Neurobiol Dis 2007, 27: 102-107. 10.1016/j.nbd.2007.04.011 Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazzella MJ, Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Ebeling C, Jiang Y, Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D: Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Natl Acad Sci U S A 2005, 102: 8972-8977. 10.1073/pnas.0500940102 Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B: Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 2006, 96: 732-742. 10.1111/j.1471-4159.2005.03578.x Wolfe MS, Kopan R: Intramembrane proteolysis: theme and variations. Science 2004, 305: 1119-1123. 10.1126/science.1096187 Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE III, Sudhof T, Yu G: Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005, 122: 435-447. 10.1016/j.cell.2005.05.022 Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H: Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A 2006, 103: 6889-6894. 10.1073/pnas.0602321103 Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ: Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 2009, 385: 642-652. 10.1016/j.jmb.2008.10.078 Sato C, Morohashi Y, Tomita T, Iwatsubo T: Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci 2006, 26: 12081-12088. 10.1523/JNEUROSCI.3614-06.2006 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: 27633-27642. 10.1074/jbc.M604997200 Sato C, Takagi S, Tomita T, Iwatsubo T: The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci 2008, 28: 6264-6271. 10.1523/JNEUROSCI.1163-08.2008 Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T: Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the gamma-secretase. J Neurosci 2010, 30: 15943-15950. 10.1523/JNEUROSCI.3318-10.2010 Watanabe N, Image I II, Takagi S, Tominaga A, Image Image I, Tomita T, Iwatsubo T: Functional analysis of the transmembrane domains of presenilin 1: participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of gamma-secretase. J Biol Chem 2010, 285: 19738-19746. 10.1074/jbc.M110.101287 Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C: The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J 2004, 23: 4738-4748. 10.1038/sj.emboj.7600478 Steiner H, Winkler E, Haass C: Chemical cross-linking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1. J Biol Chem 2008, 283: 34677-34686. 10.1074/jbc.M709067200 Takeo K, Watanabe N, Tomita T, Iwatsubo T: Contribution of the gamma-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein. J Biol Chem 2012, 287: 25834-25843. 10.1074/jbc.M111.336347 Li X, Dang S, Yan C, Gong X, Wang J, Shi Y: Structure of a presenilin family intramembrane aspartate protease. Nature 2013, 493: 56-61. Struhl G, Adachi A: Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell 2000, 6: 625-636. 10.1016/S1097-2765(00)00061-7 Bossy-Wetzel E, Schwarzenbacher R, Lipton SA: Molecular pathways to neurodegeneration. Nat Med 2004, 10(Suppl):S2-S9. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA: Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. PNAS 1999, 96: 6959-6963. 10.1073/pnas.96.12.6959 Ni CY, Murphy MP, Golde TE, Carpenter G: gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001, 294: 2179-2181. 10.1126/science.1065412 Kim DY, Ingano LA, Kovacs DM: Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage. J Biol Chem 2002, 277: 49976-49981. 10.1074/jbc.M210179200 Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C: Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem 2002, 277: 44754-44759. 10.1074/jbc.M206872200 Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK: A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002, 21: 1948-1956. 10.1093/emboj/21.8.1948 May P, Reddy YK, Herz J: Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem 2002, 277: 18736-18743. 10.1074/jbc.M201979200 Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK: A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003, 114: 635-645. 10.1016/j.cell.2003.08.008 Haapasalo A, Kovacs DM: The many substrates of presenilin/gamma-secretase. J Alzheimers Dis 2011, 25: 3-28. Artavanis-Tsakonas S, Matsuno K, Fortini ME: Notch signaling. Science 1995, 268: 225-232. 10.1126/science.7716513 Kopan R, Schroeter EH, Weintraub H, Nye JS: Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci U S A 1996, 93: 1683-1688. 10.1073/pnas.93.4.1683 Struhl G, Fitzgerald K, Greenwald I: Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell 1993, 74: 331-345. 10.1016/0092-8674(93)90424-O Kidd S, Lieber T, Young MW: Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev 1998, 12: 3728-3740. 10.1101/gad.12.23.3728 Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S: Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 1997, 89: 629-639. 10.1016/S0092-8674(00)80244-5 Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS: Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997, 387: 288-292. 10.1038/387288a0 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: A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999, 398: 518-522. 10.1038/19083 Sestan N, Artavanis-Tsakonas S, Rakic P: Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 1999, 286: 741-746. 10.1126/science.286.5440.741 Presente A, Andres A, Nye JS: Requirement of Notch in adulthood for neurological function and longevity. Neuroreport 2001, 12: 3321-3325. 10.1097/00001756-200110290-00035 Presente A, Shaw S, Nye JS, Andres AJ: Transgene-mediated RNA interference defines a novel role for notch in chemosensory startle behavior. Genesis 2002, 34: 165-169. 10.1002/gene.10149 Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, Furukawa K: Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci U S A 2004, 101: 9458-9462. 10.1073/pnas.0308126101 Salama-Cohen P, Arevalo MA, Grantyn R, Rodriguez-Tebar A: Notch and NGF/p75NTR control dendrite morphology and the balance of excitatory/inhibitory synaptic input to hippocampal neurones through Neurogenin 3. J Neurochem 2006, 97: 1269-1278. 10.1111/j.1471-4159.2006.03783.x Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G: A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002, 41: 2825-2835. 10.1021/bi015794o Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C: Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002, 21: 5408-5416. 10.1093/emboj/cdf541 Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y: Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci 2005, 25: 436-445. 10.1523/JNEUROSCI.1575-04.2005 Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawashima M, Ihara Y: Blocking the cleavage at midportion between gamma- and epsilon-sites remarkably suppresses the generation of amyloid beta-protein. FEBS Lett 2005, 579: 2907-2912. 10.1016/j.febslet.2005.04.037 Kakuda N, Funamoto S, Yagishita S, Takami M, Osawa S, Dohmae N, Ihara Y: Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J Biol Chem 2006, 281: 14776-14786. 10.1074/jbc.M513453200 Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y: gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 2009, 29: 13042-13052. 10.1523/JNEUROSCI.2362-09.2009 Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC, Ihara Y: Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry 2004, 43: 13532-13540. 10.1021/bi049399k Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS: Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996, 17: 1005-1013. 10.1016/S0896-6273(00)80230-5 Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR: Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 2004, 13: 159-170. Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M: Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. Biochemistry 2006, 45: 4907-4914. 10.1021/bi052412w Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P: TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 2006, 440: 1208-1212. 10.1038/nature04667 Wanngren J, Ottervald J, Parpal S, Portelius E, Stromberg K, Borgegard T, Klintenberg R, Jureus A, Blomqvist J, Blennow K, Zetterberg H, Lundkvist J, Rosqvist S, Karlstrom H: Second generation gamma-secretase modulators exhibit different modulation of Notch beta and Abeta production. J Biol Chem 2012, 287(39):32640-32650. 10.1074/jbc.M112.376541 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: The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J 2012, 31: 2261-2274. 10.1038/emboj.2012.79 Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ III, Kandel ER, Duff K, Kirkwood A, Shen J: Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004, 42: 23-36. 10.1016/S0896-6273(04)00182-5 Wines-Samuelson M, Schulte EC, Smith MJ, Aoki C, Liu X, Kelleher RJ III, Shen J: Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLoS One 2010, 5: e10195. 10.1371/journal.pone.0010195 Khandelwal A, Chandu D, Roe CM, Kopan R, Quatrano RS: Moonlighting activity of presenilin in plants is independent of gamma-secretase and evolutionarily conserved. Proc Natl Acad Sci U S A 2007, 104: 13337-13342. 10.1073/pnas.0702038104 Huppert SS, Ilagan MX, De Strooper B, Kopan R: Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation. Dev Cell 2005, 8: 677-688. 10.1016/j.devcel.2005.02.019 Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW, Kumar-Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T, Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, Van Broeckhoven C, Golde T, Hardy J, Haltia M, Revesz T: Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 2000, 48: 806-808. 10.1002/1531-8249(200011)48:5<806::AID-ANA18>3.0.CO;2-F Larner AJ, Doran M: Clinical phenotypic heterogeneity of Alzheimer’s disease associated with mutations of the presenilin-1 gene. J Neurol 2006, 253: 139-158. 10.1007/s00415-005-0019-5 Shepherd C, McCann H, Halliday GM: Variations in the neuropathology of familial Alzheimer’s disease. Acta Neuropathol 2009, 118: 37-52. 10.1007/s00401-009-0521-4 Huang H, He X: Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 2008, 20: 119-125. 10.1016/j.ceb.2008.01.009 Murayama M, Tanaka S, Palacino J, Murayama O, Honda T, Sun X, Yasutake K, Nihonmatsu N, Wolozin B, Takashima A: Direct association of presenilin-1 with beta-catenin. FEBS Lett 1998, 433: 73-77. 10.1016/S0014-5793(98)00886-2 Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, De Strooper B, He X, Yankner BA: Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 1998, 395: 698-702. 10.1038/27208 Cox RT, McEwen DG, Myster DL, Duronio RJ, Loureiro J, Peifer M: A screen for mutations that suppress the phenotype of Drosophila armadillo, the beta-catenin homolog. Genetics 2000, 155: 1725-1740. Noll E, Medina M, Hartley D, Zhou J, Perrimon N, Kosik KS: Presenilin affects arm/beta-catenin localization and function in Drosophila. Dev Biol 2000, 227: 450-464. 10.1006/dbio.2000.9925 Soriano S, Kang DE, Fu M, Pestell R, Chevallier N, Zheng H, Koo EH: Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J Cell Biol 2001, 152: 785-794. 10.1083/jcb.152.4.785 Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, Leibowitz G, Levine F, Koo EH: Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer’s disease-linked PS1 mutants in the beta-catenin-signaling pathway. J Neurosci 1999, 19: 4229-4237. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH: Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 2002, 110: 751-762. 10.1016/S0092-8674(02)00970-4 Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H: Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 2001, 98: 10863-10868. 10.1073/pnas.191284198 De Ferrari GV, Moon RT: The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene 2006, 25: 7545-7553. 10.1038/sj.onc.1210064 Nishimura M, Yu G, Levesque G, Zhang DM, Ruel L, Chen F, Milman P, Holmes E, Liang Y, Kawarai T, Jo E, Supala A, Rogaeva E, Xu DM, Janus C, Levesque L, Bi Q, Duthie M, Rozmahel R, Mattila K, Lannfelt L, Westaway D, Mount HT, Woodgett J, St George-Hyslop P, et al.: Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nat Med 1999, 5: 164-169. 10.1038/5526 Kawamura Y, Kikuchi A, Takada R, Takada S, Sudoh S, Shibamoto S, Yanagisawa K, Komano H: Inhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of beta-catenin phosphorylation. Eur J Biochem 2001, 268: 3036-3041. 10.1046/j.1432-1327.2001.02197.x Teo JL, Ma H, Nguyen C, Lam C, Kahn M: Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc Natl Acad Sci U S A 2005, 102: 12171-12176. 10.1073/pnas.0504600102 Ito E, Oka K, Etcheberrigaray R, Nelson TJ, McPhie DL, Tofel-Grehl B, Gibson GE, Alkon DL: Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci U S A 1994, 91: 534-538. 10.1073/pnas.91.2.534 Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK: Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 2008, 58: 871-883. 10.1016/j.neuron.2008.04.015 Stutzmann GE, Caccamo A, LaFerla FM, Parker I: 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 2004, 24: 508-513. 10.1523/JNEUROSCI.4386-03.2004 Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I: Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci 2006, 26: 5180-5189. 10.1523/JNEUROSCI.0739-06.2006 Chakroborty S, Goussakov I, Miller MB, Stutzmann GE: Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci 2009, 29: 9458-9470. 10.1523/JNEUROSCI.2047-09.2009 Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM: SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol 2008, 181: 1107-1116. 10.1083/jcb.200706171 Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I: Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 2006, 126: 981-993. 10.1016/j.cell.2006.06.059 Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I: Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest 2007, 117: 1230-1239. 10.1172/JCI30447 Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I: Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J Biol Chem 2011, 286: 22339-22347. 10.1074/jbc.M111.243063 Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK: Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 2010, 3: ra22. 10.1126/scisignal.2000818 Suzuki K, Terry RD: Fine structural localization of acid phosphatase in senile plaques in Alzheimer’s presenile dementia. Acta Neuropathol 1967, 8: 276-284. 10.1007/BF00688828 Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA: Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 1995, 14: 671-680. 10.1016/0896-6273(95)90324-0 Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM: Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005, 64: 113-122. Klionsky DJ, Emr SD: Autophagy as a regulated pathway of cellular degradation. Science 2000, 290: 1717-1721. Levine B, Klionsky DJ: Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004, 6: 463-477. 10.1016/S1534-5807(04)00099-1 Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, Zheng H, Saftig P, De Strooper B, Klumperman J, Annaert W: Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol 2004, 166: 1041-1054. 10.1083/jcb.200406060 Wilson CA, Murphy DD, Giasson BI, Zhang B, Trojanowski JQ, Lee VM: Degradative organelles containing mislocalized alpha-and beta-synuclein proliferate in presenilin-1 null neurons. J Cell Biol 2004, 165: 335-346. 10.1083/jcb.200403061 Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, Craessaerts K, De Strooper B: Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 2001, 32: 579-589. 10.1016/S0896-6273(01)00512-8 Nixon RA, Yang DS: Autophagy failure in Alzheimer’s disease–locating the primary defect. Neurobiol Dis 2011, 43: 38-45. 10.1016/j.nbd.2011.01.021 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: Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010, 141: 1146-1158. 10.1016/j.cell.2010.05.008 Neely KM, Green KN, LaFerla FM: Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a gamma-secretase-independent manner. J Neurosci 2011, 31: 2781-2791. 10.1523/JNEUROSCI.5156-10.2010 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: Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol 2012, 198: 23-35. 10.1083/jcb.201201076 Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K, Sisodia SS: A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J Neurosci 2012, 32: 8633-8648. 10.1523/JNEUROSCI.0556-12.2012 Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M: Alzheimer’s disease with spastic paresis and cotton wool type plaques. J Neurosci Res 2002, 70: 367-372. 10.1002/jnr.10392 Karlstrom H, Brooks WS, Kwok JB, Broe GA, Kril JJ, McCann H, Halliday GM, Schofield PR: Variable phenotype of Alzheimer’s disease with spastic paraparesis. J Neurochem 2008, 104: 573-583. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN: Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer’s disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 1997, 8: 1537-1542. 10.1097/00001756-199704140-00043 Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M: A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 1998, 4: 452-455. 10.1038/nm0498-452 Gant JC, Sama MM, Landfield PW, Thibault O: Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+ −induced Ca2+ release. J Neurosci 2006, 26: 3482-3490. 10.1523/JNEUROSCI.4171-05.2006 Foster TC: Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 2007, 6: 319-325. 10.1111/j.1474-9726.2007.00283.x Toescu EC, Verkhratsky A: The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging. Aging Cell 2007, 6: 267-273. 10.1111/j.1474-9726.2007.00296.x Nelson O, Supnet C, Liu H, Bezprozvanny I: Familial Alzheimer’s disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J Alzheimers Dis 2010, 21: 781-793. Supnet C, Bezprozvanny I: Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis. Sci China Life Sci 2011, 54: 744-751. 10.1007/s11427-011-4201-y Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L: Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 1999, 96: 3228-3233. 10.1073/pnas.96.6.3228 Palop JJ, Mucke L: Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 2010, 13: 812-818. 10.1038/nn.2583 Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Sudhof TC, Shen J: Presenilins are essential for regulating neurotransmitter release. Nature 2009, 460: 632-636. 10.1038/nature08177 Pratt KG, Zimmerman EC, Cook DG, Sullivan JM: Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nat Neurosci 2011, 14: 1112-1114. 10.1038/nn.2893 Dolev I, Fogel H, Milshtein H, Berdichevsky Y, Lipstein N, Brose N, Gazit N, Slutsky I: Spike bursts increase amyloid-beta 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci 2013, 16: 587-595. 10.1038/nn.3376