Skip to main content
PMC home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;4(4):249–261. doi: 10.1111/j.1582-4934.2000.tb00124.x

Neurons bearing presenilins: weapons for defense or suicide?

BO Popescu 1,b,✉, Maria Ankarcrona 1
PMCID: PMC6517821  PMID: 12067459

Abstract

Apoptotic machinery designed for cell's organized self‐destruction involve different systems of proteases which cleave vital proteins and disassemble nuclear and cytoplasmic structures, committing the cell to death. The most studied apoptotic proteolytic system is the caspase family, but calpains and the proteasome could play important roles as well. Alzheimer's disease associated presenilins showed to be a substrate for such proteolytic systems, being processed early in several apoptotic models, and recent data suggest that alternative presenilin fragments could regulate cell survival. Mutations in genes encoding presenilins proved to sensitize neurons to apoptosis by different mechanisms e.g. increased caspase‐3 activation, oxyradicals production and calcium signaling dysregulation. Here we review the data involving presenilins in apoptosis and discuss a possible role of presenilins in the regulation of apoptotic biochemical machinery.

Keywords: apoptosis, presenilin, caspase, neuron, Alzheimer's disease

References

  • 1. Drouet B., Pincon‐Raymond M., Chambaz J., Pillot T., Molecular basis of Alzheimer's disease, Cell Mol Life Sci 57:705–715, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Fraser P.E., Yang D.S., Yu G., Levesque L., Nishimura M., Arawaka S., Serpell L.C., Rogaeva E., St George‐Hyslop P., Presenilin structure, function and role in Alzheimer disease, Biochim Biophys Acta 1502:1–15, 2000. [DOI] [PubMed] [Google Scholar]
  • 3. Gandy S. and Petanceska S., Regulation of Alzheimer beta‐amyloid precursor trafficking and metabolism, Biochim Biophys Acta 1502:44–52, 2000. [DOI] [PubMed] [Google Scholar]
  • 4. Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.F., Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., Da Silva H.A.R., Haines J.L., Pericak‐Vance M.A., Tanzi R.E., Roses A.D., Fraser P.E., Rommens J.M., St George‐Hyslop P.H., Cloning of a gene bearing missense mutations in early‐onset familial Alzheimer's disease, Nature 375:754–760, 1995. [DOI] [PubMed] [Google Scholar]
  • 5. Levy‐Lahad E., Wasco W., Poorkaj P., Romano D.M., Oshima J., Pettingell W.H., Yu C.E., Jondro P.D., Schmidt S.D., Wang K., Crowley A.C., Fu Y.H., Guenette S.Y., Galas D., Nemens E., Wijsman E.M., Bird T.D., Schellenberg G.D., Tanzi R.E., Candidate gene for the chromosome 1 familial Alzheimer's disease locus, Science 269: 973–977, 1995. [DOI] [PubMed] [Google Scholar]
  • 6. Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., Fraser P.E., Rommens J.M., St George‐Hyslop P.H., Familial Alzheimer disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene, Nature 376:775–778, 1995. [DOI] [PubMed] [Google Scholar]
  • 7. Doan A., Thinakaran G., Borchelt D.R., Slunt H.H., Ratovitsky T., Podlisny M., Selkoe D.J., Seeger M., Gandy S.E., Price D.L., Sisodia S.S., Protein topology of presenilin 1, Neuron 17:1023–1030, 1996. [DOI] [PubMed] [Google Scholar]
  • 8. Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., St George‐Hyslop P., Teplow D.B., Selkoe D.J., 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 3:325–337, 1997. [DOI] [PubMed] [Google Scholar]
  • 9. Thinakaran G., Borchelt D.R., Lee M.K., Slunt H.H., Spitzer L., Kim G., Ratovitsky T., Davenport F., Nordstedt C., Seeger M., Hardy J., Levey A.I., Gandy S.E., Jenkins N.A., Copeland N.G., Price D.L., Sisodia S.S., Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo, Neuron 17:181–190, 1996. [DOI] [PubMed] [Google Scholar]
  • 10. Hong C.S. and Koo E.H., Isolation and characterization of Drosophila presenilin homolog, Neuroreport 8:665–668, 1997. [DOI] [PubMed] [Google Scholar]
  • 11. Boulianne G.L., Livne‐Bar I., Humphreys J.M., Liang Y., Lin C., Rogaev E., St George‐Hyslop P., Cloning and characterization of the Drosophila presenilin homologue, Neuroreport 3:1025–1029, 1997. [DOI] [PubMed] [Google Scholar]
  • 12. Levitan D., Doyle T.G., Brousseau D., Lee M.K., Thinakaran G., Slunt H.H., Sisodia S.S., Greenwald I., Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc Natl Acad Sci U S A 93:14940–14944, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Li X. and Greenwald I., Membrane topology of the C. elegans SEL‐12 presenilin, Neuron 17:1015–1021, 1996. [DOI] [PubMed] [Google Scholar]
  • 14. Okochi M., Sahara N., Kametani F., Usami M., Arai T., Tanaka K., Ishii K., Yamamoto A., Mori H, Presenilin 1 cleavage is a universal event in human organs, Neurobiol Aging 19:S3–10, 1998. [DOI] [PubMed] [Google Scholar]
  • 15. Lee M.K., Slunt H.H., Martin L.J., Thinakaran G., Kim G., Gandy S.E., Seeger M., Koo E., Price D.L., Sisodia S.S., Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues, J Neurosci 16:7513–7525, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Lah J.J., Heilman C.J., Nash N.R., Rees H.D., Yi H., Counts S.E., Levey A.I., Light and electron microscopic localization of presenilin‐1 in primate brain, J Neurosci 17:1971–1980, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Kovacs D.M., Fausett H.J., Page K.J., Kim T.W., Moir R.D., Merriam D.E., Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., Tanzi R.E., Wasco W., Alzheimer‐associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells, Nat Med 2:224–229, 1996. [DOI] [PubMed] [Google Scholar]
  • 18. Culvenor J.G., Maher F., Evin G., Malchiodi‐Albedi F., Cappai R., Underwood J.R., Davis J.B., Karran E.H., Roberts G.W., Beyreuther K., Masters C.L., Alzheimer's disease‐associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum‐Golgi intermediate compartment, J Neurosci Res 49:719–731, 1997. [DOI] [PubMed] [Google Scholar]
  • 19. Li J., Xu M., Zhou H., Ma J., Potter H., Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation, Cell 90:917–927, 1997. [DOI] [PubMed] [Google Scholar]
  • 20. Dewji N.N., Singer S.J., Cell surface expression of the Alzheimer disease‐related presenilin proteins, Proc Natl Acad Sci U S A 94:9926–9931, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Blanchard V., Czech C., Bonici B., Clavel N., Gohin M., Dalet K., Revah F., Pradier L., Imperato A., Moussaoui S., Immunohistochemical analysis of presenilin 2 expression in the mouse brain: distribution pattern and co‐localization with presenilin 1 protein, Brain Res 758:209–217, 1997. [DOI] [PubMed] [Google Scholar]
  • 22. Oppenheim R.W., Cell death during development of the nervous system, Annu. Rev. Neurosci. 14:453–501, 1991. [DOI] [PubMed] [Google Scholar]
  • 23. Kuan C.Y., Roth K.A., Flavell R.A., Rakic P., Mechanisms of programmed cell death in the developing brain, Trends Neurosci 23:291–297, 2000. [DOI] [PubMed] [Google Scholar]
  • 24. Moreno‐Flores M.T., Medina M., Wandosell F., Expression of presenilin 1 in nervous system during rat development, J Comp Neurol 410:556–570, 1999. [PubMed] [Google Scholar]
  • 25. Kuida K., Haydar T.F., Kuan C.Y., Gu Y., Taya C., Karasuyama H., Su M.S., Rakic P., Flavell R.A., Reduced apoptosis and cytochrome c‐mediated caspase activation in mice lacking caspase 9, Cell 94:325–337, 1998. [DOI] [PubMed] [Google Scholar]
  • 26. Clapham D.E., Calcium signaling, Cell 80:259–268, 1995. [DOI] [PubMed] [Google Scholar]
  • 27. Ankarcrona M., Dypbukt J.M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S.A., Nicotera P., Glutamate‐induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function, Neuron 15:961–973, 1995. [DOI] [PubMed] [Google Scholar]
  • 28. Nicotera P. and Orrenius S., The role of calcium in apoptosis, Cell Calcium 23:173–180, 1998. [DOI] [PubMed] [Google Scholar]
  • 29. Gibson G.E. and Peterson C., Calcium and the aging nervous system, Neurobiol Aging 8:329–43, 1987. [DOI] [PubMed] [Google Scholar]
  • 30. Khachaturian Z.S., Calcium and the aging brain: upsetting a delicate balance?, Geriatrics 46:78–79, 1991. [PubMed] [Google Scholar]
  • 31. Verkhratsky A. and Toescu E.C., Calcium and neuronal ageing, Trends Neurosci 21:2–7, 1998. [DOI] [PubMed] [Google Scholar]
  • 32. Tanzi R.E., Of calcium, caspases, and cognitive decline, Nat Med 4:1127–1128, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. Guo Q., Furukawa K., Sopher B.L., Pham D.G., Xie J., Robinson N., Martin G.M., Mattson M.P., Alzheimer's PS‐1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta‐peptide, Neuroreport 8:379–383, 1996. [DOI] [PubMed] [Google Scholar]
  • 34. Ito E., Oka K., Etcheberrigaray R., Nelson T.J., McPhie D.L., Tofel‐Grehl B., Gibson G.E., Alkon D.L., Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease, Proc Natl Acad Sci U S A 91:534–538, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Hirashima N., Etcheberrigaray R., Bergamaschi S., Racchi M., Battaini F., Binetti G., Govoni S., Alkon D.L., Calcium responses in human fibroblasts: a diagnostic molecular profile for Alzheimer's disease, Neurobiol Aging 17:549–555, 1996. [DOI] [PubMed] [Google Scholar]
  • 36. Keller J.N., Guo Q., Holtsberg F.W., Bruce‐Keller A.J., Mattson M.P., Increased sensitivity to mitochondrial toxin‐induced apoptosis in neural cells expressing mutant presenilin‐1 is linked to perturbed calcium homeostasis and enhanced oxyradical production, J Neurosci 18:4439–4450, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Guo Q., Christakos S., Robinson N., Mattson M.P., Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function, Proc Natl Acad Sci U S A 95:3227–3232, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Leissring M.A., Paul B.A., Parker I., Cotman C.W., LaFerla F.M., Alzheimer's presenilin‐1 mutation potentiates inositol 1,4,5‐trisphosphate‐mediated calcium signaling in Xenopus oocytes, J Neurochem 72:1061–1068, 1999. [DOI] [PubMed] [Google Scholar]
  • 39. Van der Bliek A.M., Meyers M.B., Biedler J.L., Hes E., Borst P., A 22‐kd protein (sorcin/V19) encoded by an amplified gene in multidrug‐resistant cells, is homologous to the calcium‐binding light chain of calpain, EMBO J 5:3201–3208, 1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Pickel V.M., Clarke C.L., Meyers M.B., Ultrastructural localization of sorcin, a 22 kDa calcium binding protein, in the rat caudate‐putamen nucleus: association with ryanodine receptors and intracellular calcium release, J Comp Neurol 386:625–634, 1997. [DOI] [PubMed] [Google Scholar]
  • 41. Gracy K.N., Clarke C.L., Meyers M.B., Pickel V.M., N‐methyl‐D‐aspartate receptor 1 in the caudate‐putamen nucleus: ultrastructural localization and co‐expression with sorcin, a 22,000 mol. wt calcium binding protein, Neuroscience 90:107–117, 1999. [DOI] [PubMed] [Google Scholar]
  • 42. Pack‐Chung E., Meyers M.B., Pettingell W.P., Moir R.D., Brownawell A.M., Cheng I., Tanzi R.E., Kim T.W., Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor, J Biol Chem 275:14440–14445, 2000. [DOI] [PubMed] [Google Scholar]
  • 43. Buxbaum J.D., Choi E.K., Luo Y., Lilliehook C., Crowley A.C., Merriam D.E., Wasco W., Calsenilin: a calcium‐binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment, Nat Med 4:1177–1181, 1998. [DOI] [PubMed] [Google Scholar]
  • 44. Vito P., Ghayur T., D'Adamio L., Generation of antiapoptotic presenilin‐2 polypeptides by alternative transcription, proteolysis, and caspase‐3 cleavage, J Biol Chem 272:28315–28320, 1997. [DOI] [PubMed] [Google Scholar]
  • 45. van Gassen G., Annaert W., van Broeckhoven C., Binding partners of Alzheimer's disease proteins: are they physiologically relevant?, Neurobiol Dis 7:135–151, 2000. [DOI] [PubMed] [Google Scholar]
  • 46. Adams J.M. and Cory S., The Bcl‐2 protein family: arbiters of cell survival, Science 281:1322–1326, 1998. [DOI] [PubMed] [Google Scholar]
  • 47. Alberici A., Moratto D., Benussi L., Gasparini L., Ghidoni R., Gatta L.B., Finazzi D., Frisoni G.B., Trabucchi M., Growdon J.H., Nitsch R.M., Binetti G., Presenilin 1 protein directly interacts with Bcl‐2, J Biol Chem 274:30764–30769, 1999. [DOI] [PubMed] [Google Scholar]
  • 48. Passer B.J., Pellegrini L., Vito P., Ganjei J.K., D'Adamio L., Interaction of Alzheimer's presenilin‐1 and presenilin‐2 with Bcl‐X(L). A potential role in modulating the threshold of cell death, J Biol Chem 274:24007–24013, 1999. [DOI] [PubMed] [Google Scholar]
  • 49. Dierick H. and Bejsovec A., Cellular mechanisms of wingless/Wnt signal transduction, Curr Top Dev Biol 43:153–190, 1999. [DOI] [PubMed] [Google Scholar]
  • 50. Zhou J., Liyanage U., Medina M., Ho C., Simmons A.D., Lovett M., Kosik K.S., Presenilin 1 interaction in the brain with a novel member of the Armadillo family, Neuroreport 8:2085–2090, 1997. [DOI] [PubMed] [Google Scholar]
  • 51. 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 433:73–77, 1998. [DOI] [PubMed] [Google Scholar]
  • 52. Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., Liang Y., Rogaeva E., Ikeda M., Duthie M., Murgolo N., Wang L., VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., St George‐Hyslop P., Presenilins interact with armadillo proteins including neural‐specific plakophilin‐related protein and beta‐catenin, J Neurochem 72:999–1008, 1999. [DOI] [PubMed] [Google Scholar]
  • 53. Stahl B., Diehlmann A., Sudhof T.C., Direct interaction of Alzheimer's disease‐related presenilin 1 with armadillo protein p0071, J Biol Chem 274:9141–9148, 1999. [DOI] [PubMed] [Google Scholar]
  • 54. Zhang Z., Hartmann H., Do V.M., Abramowski D., Sturchler‐Pierrat C., Staufenbiel M., Sommer B., van de Wetering M., Clevers H., Saftig P., De Strooper B., He X., Yankner B.A., Destabilization of beta‐catenin by mutations in presenilin‐1 potentiates neuronal apoptosis, Nature 395:698–702, 1998. [DOI] [PubMed] [Google Scholar]
  • 55. Brancolini C., Lazarevic D., Rodriguez J., Schneider C., Dismantling cell‐cell contacts during apoptosis is coupled to a caspase‐dependent proteolytic cleavage of betacatenin, J Cell Biol 139:759–771, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. van de Craen M., de Jonghe C., van den Brande I., Declercq W., van Gassen G., van Criekinge W., Vanderhoeven I., Fiers W., van Broeckhoven C., Hendriks L., Vandenabeele P., Identification of caspases that cleave presenilin‐1 and presenilin‐2. Five presenilin‐1 (PS1) mutations do not alter the sensitivity of PS1 to caspases, FEBS Lett 445:149–154, 1999. [DOI] [PubMed] [Google Scholar]
  • 57. Maruyama K., Usami M., Kametani F., Tomita T., Iwatsubo T., Saido T.C., Mori H., Ishiura S., Molecular interactions between presenilin and calpain: inhibition of m‐calpain protease activity by presenilin‐1, 2 and cleavage of presenilin‐1 by m‐, mu‐calpain, Int J Mol Med 5:269–273, 2000. [DOI] [PubMed] [Google Scholar]
  • 58. Fraser P.E., Levesque G., Yu G., Mills L.R., Thirlwell J., Frantseva M., Gandy S.E., Seeger M., Carlen P.L., St George‐Hyslop P., Presenilin 1 is actively degraded by the 26S proteasome, Neurobiol Aging 19:S19–21, 1998. [DOI] [PubMed] [Google Scholar]
  • 59. Vezina J., Tschopp C., Andersen E., Muller K., Overexpression of a C‐terminal fragment of presenilin 1 delays anti‐Fas induced apoptosis in Jurkat cells, Neurosci Lett 263:65–68, 1999. [DOI] [PubMed] [Google Scholar]
  • 60. Popescu B.O., Cedazo‐Minguez A., Popescu L.M., Winblad B., Cowburn R.F., Ankarcrona M., Caspase Cleavage of Exon 9 Deleted Presenilin‐1 Is an Early Event in Apoptosis Induced by Calcium Ionophore A 23187 in SH‐SY5Y Neuroblastoma Cells, submitted manuscript. [DOI] [PubMed]
  • 61. Janicki S. and Monteiro M.J., Increased apoptosis arising from increased expression of the Alzheimer's disease‐associated presenilin‐2 mutation (N141I), J Cell Biol 139:485–495, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Janicki S.M. and Monteiro M.J., 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 155:135–144, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Janicki S.M., Stabler S.M., Monteiro M.J., Familial Alzheimer's disease presenilin‐1 mutants potentiate cell cycle arrest, Neurobiol Aging 21:829–836, 2000. [DOI] [PubMed] [Google Scholar]
  • 64. Walter J., Schindzielorz A., Grunberg J., Haass C., Phosphorylation of presenilin‐2 regulates its cleavage by caspases and retards progression of apoptosis, Proc Natl Acad Sci U S A 96:1391–1396, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. De Strooper B. and Annaert W., Proteolytic processing and cell biological functions of the amyloid precursor protein, J Cell Sci 113:1857–1870, 2000. [DOI] [PubMed] [Google Scholar]
  • 66. Forloni G., Chiesa R., Smiroldo S., Verga L., Salmona M., Tagliavini F., Angeretti N., Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35, Neuroreport 4:523–526, 1993. [DOI] [PubMed] [Google Scholar]
  • 67. Loo D.T., Copani A., Pike C.J., Whittemore E.R., Walencewicz A.J., Cotman C.W., Apoptosis is induced by beta‐amyloid in cultured central nervous system neurons, Proc Natl Acad Sci U S A 90:7951–7955, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Watt J.A., Pike C.J., Walencewicz‐Wasserman A.J., Cotman C.W., Ultrastructural analysis of beta‐amyloid‐induced apoptosis in cultured hippocampal neurons, Brain Res 661:147–156, 1994. [DOI] [PubMed] [Google Scholar]
  • 69. Anderson A.J., Pike C.J., Cotman C.W., Differential induction of immediate early gene proteins in cultured neurons by beta‐amyloid (A beta): association of c‐Jun with A beta‐induced apoptosis, J Neurochem 65:1487–1498, 1995. [DOI] [PubMed] [Google Scholar]
  • 70. Scheuner D., Eckman C., Jensen M., Song X., Citron M., Suzuki N., Bird T.D., 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 2:864–870, 1996. [DOI] [PubMed] [Google Scholar]
  • 71. Vassar R., Bennett B.D., Babu‐Khan S., Kahn S., Mendiaz E.A., Denis P., Teplow D.B., Ross S., Amarante P., Loeloff R., Luo Y., Fisher S., Fuller J., Edenson S., Lile J., Jarosinski M.A., Biere A.L., Curran E., Burgess T., Louis J.C., Collins F., Treanor J., Rogers G., Citron M., Beta‐secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE, Science 286:735–741, 1999. [DOI] [PubMed] [Google Scholar]
  • 72. Hussain I., Powell D., Howlett D.R., Tew D.G., Meek T.D., Chapman C., Gloger I.S., Murphy K.E., Southan C.D., Ryan D.M., Smith T.S., Simmons D.L., Walsh F.S., Dingwall C., Christie G., Identification of a novel aspartic protease (Asp 2) as beta‐secretase, Mol Cell Neurosci 14:419–427, 1999. [DOI] [PubMed] [Google Scholar]
  • 73. 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 2:461–462, 2000. [DOI] [PubMed] [Google Scholar]
  • 74. Zhang Z., Nadeau P., Song W., Donoviel D., Yuan M., Bernstein A., Yankner B.A., Presenilins are required for gamma‐secretase cleavage of beta‐APP and transmembrane cleavage of Notch‐1, Nat Cell Biol 2:463–465, 2000. [DOI] [PubMed] [Google Scholar]
  • 75. Esler W.P., Kimberly W.T., Ostaszewski B.L., Diehl T.S., Moore C.L., Tsai J.Y., Rahmati T., Xia W., Selkoe D.J., Wolfe M.S., Transition‐state analogue inhibitors of gamma‐secretase bind directly to presenilin‐1, Nat Cell Biol 2:428–434, 2000. [DOI] [PubMed] [Google Scholar]
  • 76. Li Y.M., Xu M., Lai M.T., Huang Q., Castro J.L., DiMuzio‐Mower J., Harrison T., Lellis C., Nadin A., Neduvelil J.G., Register R.B., Sardana M.K., Shearman M.S., Smith A.L., Shi X.P., Yin K.C., Shafer J.A., Gardell S.J., Photoactivated gamma‐secretase inhibitors directed to the active site covalently label presenilin 1, Nature 405:689–694, 2000. [DOI] [PubMed] [Google Scholar]
  • 77. Guo Q., Sopher B.L., Furukawa K., Pham D.G., Robinson N., Martin G.M., Mattson M.P., Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid betapeptide: involvement of calcium and oxyradicals, J Neurosci 17:4212–4222, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Guo Q., Robinson N., Mattson M.P., Secreted beta‐amyloid precursor protein counteracts the proapoptotic action of mutant presenilin‐1 by activation of NF‐kappaB and stabilization of calcium homeostasis, J Biol Chem 273:12341–12351, 1998. [DOI] [PubMed] [Google Scholar]
  • 79. Guo Q., Christakos S., Robinson N., Mattson M.P., Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function, Proc Natl Acad Sci U S A 95:3227–3232, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Guo Q., Sebastian L., Sopher B.L., Miller M.W., Ware C.B., Martin G.M., Mattson M.P., Increased vulnerability of hippocampal neurons from presenilin‐1 mutant knock‐in mice to amyloid beta‐peptide toxicity: central roles of superoxide production and caspase activation, J Neurochem 72:1019–1029, 1999. [DOI] [PubMed] [Google Scholar]
  • 81. Guo Q., Fu W., Holtsberg F.W., Steiner S.M., Mattson M.P., Superoxide mediates the cell‐death‐enhancing action of presenilin‐1 mutations, J Neurosci Res 56:457–470, 1999. [DOI] [PubMed] [Google Scholar]
  • 82. Wolozin B., Alexander P., Palacino J., Regulation of apoptosis by presenilin 1, Neurobiol Aging 19:S23–S27, 1998. [DOI] [PubMed] [Google Scholar]
  • 83. Weihl C.C., Ghadge G.D., Kennedy S.G., Hay N., Miller R.J., Roos R.P., Mutant presenilin‐1 induces apoptosis and downregulates Akt/PKB, J Neurosci 19:5360–5369, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Weihl C.C., Miller R.J., Roos R.P., The role of betacatenin stability in mutant PS1‐associated apoptosis, Neuroreport 10:2527–2532, 1999. [DOI] [PubMed] [Google Scholar]
  • 85. Kovacs D.M., Mancini R., Henderson J., Na S.J., Schmidt S.D., Kim T.W., Tanzi R.E., Staurosporine‐induced activation of caspase‐3 is potentiated by presenilin 1 familial Alzheimer's disease mutations in human neuroglioma cells, J Neurochem 73:2278–2285, 1999. [DOI] [PubMed] [Google Scholar]
  • 86. Tanii H., Ankarcrona M., Flood F., Nilsberth C., Mehta N.D., Perez‐Tur J., Winblad B., Benedikz E., Cowburn R.F., Alzheimer's disease presenilin‐1 exon 9 deletion and L250S mutations sensitize SH‐SY5Y neuroblastoma cells to hyperosmotic stress‐induced apoptosis, Neuroscience 95:593–601, 2000. [DOI] [PubMed] [Google Scholar]
  • 87. Mattson M.P., Zhu H., Yu J., Kindy M.S., Presenilin‐1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis, J Neurosci 20:1358–1364, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Mattson M.P., Robinson N., Guo Q., Estrogens stabilize mitochondrial function and protect neural cells against the pro‐apoptotic action of mutant presenilin‐1, Neuroreport 8:3817–3821, 1997. [DOI] [PubMed] [Google Scholar]
  • 89. Wolozin B., Iwasaki K., Vito P., Ganjei J.K., Lacana E., Sunderland T., Zhao B., Kusiak J.W., Wasco W., D'Adamio L., Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation, Science 274:1710–1713, 1996. [DOI] [PubMed] [Google Scholar]
  • 90. Chan S.L., Mayne M., Holden C.P., Geiger J.D., Mattson M.P., Presenilin‐1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons, J Biol Chem 275:18195–18200, 2000. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES