Advertisement

Molecular Medicine

, Volume 21, Supplement 1, pp S41–S48 | Cite as

Twenty Years of Presenilins—Important Proteins in Health and Disease

  • Jochen Walter
Invited Review Article

Abstract

Alzheimer’s disease (AD) is characterized by progressive decline in cognitive functions associated with depositions of aggregated proteins in the form of extracellular plaques and neurofibrillary tangles in the brain. Extracellular plaques contain characteristic fibrils of amyloid β peptides (Aβ); tangles consist of paired helical filaments of the microtubuli-associated protein tau. Although AD manifests predominantly at ages above 65 years, rare cases show a much earlier onset of disease symptoms with very similar neuropathological characteristics. In 1995, two homologous genes were identified, in which mutations are associated with dominantly inherited familial forms of early onset AD. The genes therefore were dubbed presenilins (PS) and encode polytopic transmembrane proteins. At this time the role of these proteins in the pathogenesis of AD and their biological function in general were completely unknown. However, individuals carrying PS mutations showed alterations in the composition of different length variants of Aβ peptides in blood and cerebrospinal fluid, which indicated the potential involvement of presenilins in the metabolism of Aβ. After 20 years of intense research, the roles of presenilins in Aβ generation as well as important functions in biological processes have been identified. Presenilins represent the catalytic components of protease complexes that directly cleave the amyloid precursor protein (APP) but also many other proteins with important physiological functions. Here, the progress in presenilin research from basic characterization of their cellular functions to the targeting in clinical trials for AD therapy, and potential future directions, will be discussed.

Notes

Acknowledgments

I am grateful to my colleagues for interesting discussions and fruitful collaborations. Especially, I would like to thank C Haass for initiation of and guidance through presenilin research for many years. I also thank previous and current lab members for their excellent work and stimulating discussions.

The lab is or was supported by grants of the German Research Foundation (DFG), the German Federal Ministry for Education and Research (BMBF), the Mizutani Foundation, and the Hans and Ilse Breuer Foundation.

References

  1. 1.
    Selkoe D, Mandelkow E, Holtzman D. (2012) Deciphering Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a011460.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Querfurth HW, LaFerla FM. (2010) Alzheimer’ s disease. N. Engl. J. Med. 362:329–44.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Kennedy JL, Farrer LA, Andreasen NC, Mayeux R, St George-Hyslop P. (2003) The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science. 302:822–6.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Tanzi RE. (2012) The genetics of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006296.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Goate A, Hardy J. (2012) Twenty years of Alzheimer’s disease-causing mutations. J. Neurochem. 120 (Suppl 1):3–8.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Glenner GG, Wong CW. (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120:885–90.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Masters CL, et al. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U. S. A. 82:4245–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Kang J, et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 325:733–6.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Haass C, Kaether C, Thinakaran G, Sisodia S. (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2:a006270.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    De Strooper B, Vassar R, Golde T. (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6:99–107.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Walter J, Kaether C, Steiner H, Haass C. (2001) The cell biology of Alzheimer’s disease: uncovering the secrets of secretases. Curr. Opin. Neurobiol. 11:585–90.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Goate et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 349:704–6.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hardy J, Selkoe DJ. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 297:353–6.CrossRefGoogle Scholar
  14. 14.
    Sherrington R, et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 375:754–60.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Rogaev EI, et al. (1995) 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. 376:775–8.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Levy-Lahad E, et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 269:973–7.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Scheuner D, et al. (1996) Secreted amyloid betaprotein 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. 2:864–70.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Borchelt DR, et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1–42/1–40 ratio in vitro and in vivo. Neuron. 17:1005–13.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Holcomb L, et al. (1998) Accelerated Alzheimertype phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4:97–100.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Tomita T, et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. U. S. A. 94:2025–30.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Oyama F, et al. (1998) Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid beta-protein 42 in the brain. J. Neurochem. 71:313–22.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Mehta ND, et al. (1998) Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann. Neurol. 43:256–8.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Kovacs DM, et al. (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat. Med. 2:224–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Walter J, et al. (1996) The Alzheimer’s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol. Med. 2:673–91.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    De Strooper B, et al. (1997) Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer’s disease-associated presenilins. J. Biol. Chem. 272:3590–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Weidemann A, et al. (1997) Formation of stable complexes between two Alzheimer’s disease gene products: presenilin-2 and beta-amyloid precursor protein. Nat. Med. 3:328–32.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. (1997) Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 94:8208–13.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Walter J, Grunberg J, Schindzielorz A, Haass C. (1998) Proteolytic fragments of the Alzheimer’s disease associated presenilins-1 and -2 are phosphorylated in vivo by distinct cellular mechanisms. Biochemistry. 37:5961–7.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Thinakaran G, et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 17:181–90.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Lee MK, et al. (1996) Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. J. Neurosci. 16:7513–25.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Mercken M, et al. (1996) Characterization of human presenilin 1 using N-terminal specific monoclonal antibodies: evidence that Alzheimer mutations affect proteolytic processing. FEBS Lett. 389:297–303.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Ward RV, et al. (1996) Presenilin-1 is processed into two major cleavage products in neuronal cell lines. Neurodegeneration. 5:293–8.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Walter J, et al. (1997) Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc. Natl. Acad. Sci. U. S. A. 94:5349–54.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Seeger M, et al. (1997) Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc. Natl. Acad. Sci. U. S. A. 94:5090–4.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Levitan D, Greenwald I. (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature. 377:351–4.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Levitan D, et al. (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 93:14940–4.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Baumeister R, et al. (1997) Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1:149–59.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Shen J, et al. (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 89:629–39.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Wong PC, et al. (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 387:288–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Herreman A, et al. (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. 96:11872–7.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mumm JS, Kopan R (2000) Notch signaling: from the outside in. Dev. Biol. 228:151–65.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Hori K, Sen A, Artavanis-Tsakonas S. (2013) Notch signaling at a glance. J. Cell Sci. 126:2135–40.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    De Strooper B, et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 391:387–90.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Wolfe MS, et al. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 398:513–7.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Struhl G, Greenwald I. (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 398:522–5.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    De Strooper B, et al. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 398:518–22.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Ye Y, Lukinova N, Fortini ME. (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature. 398:525–9.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Struhl G, Adachi A. (1998) Nuclear access and action of notch in vivo. Cell. 93:649–60.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Koo EH, Squazzo SL. (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J. Biol. Chem. 269:17386–9.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Lai A, Sisodia SS, Trowbridge IS. (1995) Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain. J. Biol. Chem. 270:3565–73.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Yamazaki T, Selkoe DJ, Koo EH. (1995) Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J. Cell Biol. 129:431–42.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Wild-Bode C, et al. (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J. Biol. Chem. 272:16085–8.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Annaert WG, et al. (1999) Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons. J. Cell Biol. 147:277–94.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kaether C, et al. (2002) Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. J. Cell Biol. 158:551–61.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wang Y, et al. (2004) Involvement of Notch signaling in hippocampal synaptic plasticity. Proc. Natl. Acad. Sci. U. S. A. 101:9458–62.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Vetrivel KS, et al. (2004) Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J. Biol. Chem. 279:44945–54.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Podlisny MB, et al. (1997) 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. 3:325–37.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Marambaud P, Ancolio K, Lopez-Perez E, Checler F. (1998) Proteasome inhibitors prevent the degradation of familial Alzheimer’s disease-linked presenilin 1 and potentiate A beta 42 recovery from human cells. Mol. Med. 4:147–57.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Capell A, et al. (1998) The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J. Biol. Chem. 273:3205–11.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Steiner H, et al. (1998) Expression of Alzheimer’s disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J. Biol. Chem. 273:32322–31.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Thinakaran G, et al. (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272:28415–22.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Wolozin B, et al. (1996) Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science. 274:1710–3.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Zhou J, et al. (1997) Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport. 8:1489–94.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Yu G, et al. (1998) The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J. Biol. Chem. 273:16470–5.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Takashima A, et al. (1998) Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. U. S. A. 95:9637–41.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yu G, et al. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 407:48–54.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Francis R, et al. (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev. Cell. 3:85–97.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Edbauer D, et al. (2003) Reconstitution of gamma-secretase activity. Nat. Cell Biol. 5:486–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Kimberly WT, et al. (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. U. S. A. 100:6382–7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Takasugi N, et al. (2003) The role of presenilin co-factors in the gamma-secretase complex. Nature. 422:438–41.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Haass C, Steiner H. (2002) Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell. Biol. 12:556–62.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    De Strooper B, Annaert W. (2010) Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu. Rev. Cell Dev. Biol. 26:235–60.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    St George-Hyslop P, Fraser PE. (2012) Assembly of the presenilin gamma-/epsilon-secretase complex. J. Neurochem. 120 (Suppl 1):84–8.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Haapasalo A, Kovacs DM. (2011) The many substrates of presenilin/gamma-secretase. J. Alzheimers Dis. 25:3–28.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kopan R, Ilagan MX. (2004) Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell. Biol. 5:499–504.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Wolfe MS. (2007) When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 8:136–40.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Shen J, Kelleher RJ III. (2007) The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl. Acad. Sci. U. S. A. 104:403–9.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Mertens J, et al. (2013) APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based gamma-secretase modulation. Stem Cell Reports. 1:491–8.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Koch P, et al. (2012) Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of gamma-secretase activity in endogenous amyloid-beta generation. Am. J. Pathol. 180:2404–16.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Morishima-Kawashima M. (2014) Molecular mechanism of the intramembrane cleavage of the beta-carboxyl terminal fragment of amyloid precursor protein by gamma-secretase. Front. Physiol. 5:463.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. (2010) Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J. Neurosci. 30:14946–54.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Robakis NK. (2011) Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol. Aging. 32:372–9.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Vito P, Lacana E, D’Adamio L. (1996) Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer’s disease gene ALG-3. Science. 271:521–5.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Grunberg J, et al. (1998) Alzheimer’s disease associated presenilin-1 holoprotein and its 18–20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry. 37:2263–70.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. (1997) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science. 277:373–6.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Loetscher H, et al. (1997) Presenilins are processed by caspase-type proteases. J. Biol. Chem. 272:20655–9.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Vito P, Ghayur T, D’Adamio L. (1997) Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. J. Biol. Chem. 272:28315–20.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Walter J, Schindzielorz A, Grunberg J, Haass C. (1999) Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis. Proc. Natl. Acad. Sci. U. S. A. 96:1391–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Fluhrer R, et al. (2003) Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. J. Biol. Chem. 278:5531–8.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV. (2001) Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276:30701–7.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV. (2001) Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling. J. Biol. Chem. 276:7366–75.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Prager K, et al. (2007) A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling. J. Biol. Chem. 282:14083–93.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Zhang Z, et al. (1998) Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature. 395:698–702.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Nishimura M, et al. (1999) Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nat. Med. 5:164–9.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Kang DE, et al. (1999) 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. 19:4229–37.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Kang DE, et al. (2002) Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 110:751–62.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Matz A, et al. (2015) Identification of new Presenilin-1 phosphosites: implication for gamma-secretase activity and Abeta production. J. Neurochem. 133:409–21.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Guo Q, Robinson N, Mattson MP. (1998) 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. 273:12341–51.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Leissring MA, et al. (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149:793–8.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Honarnejad K, Herms J. (2012) Presenilins: role in calcium homeostasis. Int. J. Biochem. Cell Biol. 44:1983–6.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    LaFerla FM. (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat. Rev. Neurosci. 3:862–72.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Mattson MP. (2010) ER calcium and Alzheimer’s disease: in a state of flux. Sci. Signal. 3:e10.CrossRefGoogle Scholar
  103. 103.
    Leissring MA, et al. (2002) A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APP. Proc. Natl. Acad. Sci. U. S. A. 99:4697–702.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    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. 275:18195–200.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Tu H, et al. (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell. 126:981–93.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Shilling D, Mak DO, Kang DE, Foskett JK. (2012) Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. J. Biol. Chem. 287:10933–44.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Brunello L, et al. (2009) Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake. J. Cell. Mol. Med. 13:3358–69.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Cheung KH, et al. (2008) Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 58:871–83.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    McCombs JE, Gibson EA, Palmer AE. (2010) Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics. Mol. Biosyst. 6:1640–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Popugaeva E, Bezprozvanny I. (2013) Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease. Front. Mol. Neurosci. 6:29.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Bezprozvanny I, Mattson MP. (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31:454–63.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Green KN, LaFerla FM. (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron. 59:190–4.CrossRefGoogle Scholar
  113. 113.
    Naruse S, et al. (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron. 21:1213–21.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Esselens C, et al. (2004) Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J. Cell Biol. 166:1041–54.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Lee JH, et al. (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 141:1146–58.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Coen K, et al. (2012) Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198:23–35.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Zhang X, et al. (2012) A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J. Neurosci. 32:8633–48.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Orr ME, Oddo S. (2013) Autophagic/lysosomal dysfunction in Alzheimer’s disease. Alzheimers Res. Ther. 5:53.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Selkoe DJ. (2013) The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann. Neurol. 74:328–36.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Doody RS, et al. (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369:341–50.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    De Strooper B. (2014) Lessons from a failed gamma-secretase Alzheimer trial. Cell. 159:721–6.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Karran E, Hardy J. (2014) A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann. Neurol. 76:185–205.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Saura CA, et al. (2004) Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 42:23–36.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Weggen S, et al. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 414:212–6.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Mullane K, Williams M. (2013) Alzheimer’s therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem. Pharmacol. 85:289–305.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Tamboli IY, et al. (2008) Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis. J. Neurosci. 28:12097–106.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Wunderlich P, et al. (2013) Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 288:33027–36.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Kleinberger G, et al. (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6:243ra86.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Lu P, et al. (2014) Three-dimensional structure of human gamma-secretase. Nature. 512:166–70.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Sun L, et al. (2015) Structural basis of human gamma-secretase assembly. Proc. Natl. Acad. Sci. U. S. A. 112:6003–8.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Li Y, et al. (2014) Structural biology of presenilin 1 complexes. Mol. Neurodegener. 9:59.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of BonnBonnGermany

Personalised recommendations