Abstract

Presenilin-1 (PSEN1) is the catalytic subunit of the γ-secretase complex, and pathogenic mutations in the PSEN1 gene account for the majority cases of familial AD (FAD). FAD-associated mutant PSEN1 proteins have been shown to affect APP processing and Aβ generation and inhibit Notch1 cleavage and Notch signaling. In this report, we found that a PSEN1 mutation (S169del) altered APP processing and Aβ generation, and promoted neuritic plaque formation as well as learning and memory deficits in AD model mice. However, this mutation did not affect Notch1 cleavage and Notch signaling in vitro and in vivo. Taken together, we demonstrated that PSEN1S169del has distinct effects on APP processing and Notch1 cleavage, suggesting that Notch signaling may not be critical for AD pathogenesis and serine169 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch1 cleavage to treat AD.

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References

  1. 1.

    Zhang S, Wang Z, Cai F, Zhang M, Wu Y, Zhang J, et al. BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J Neurosci. 2017;37:6915–25.

  2. 2.

    Deng Y, Wang Z, Wang R, Zhang X, Zhang S, Wu Y, et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci. 2013;37:1962–9.

  3. 3.

    Sun X, He G, Song W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome. FASEB J. 2006;20:1369–76.

  4. 4.

    Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, et al. Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest. 2013;123:224–35.

  5. 5.

    Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med. 2008;205:2781–9.

  6. 6.

    Zeng J, Chen L, Wang Z, Chen Q, Fan Z, Jiang H, et al. Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis. Acta Neuropathol. 2017;133:967–82.

  7. 7.

    Mullard A. BACE inhibitor bust in Alzheimer trial. Nat Rev Drug Discov. 2017;16:155.

  8. 8.

    Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50.

  9. 9.

    Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414:212–6.

  10. 10.

    Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, et al. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci USA. 2003;100:12444–9.

  11. 11.

    He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature. 2010;467:95–98.

  12. 12.

    Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem. 2005;280:41987–96.

  13. 13.

    Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, et al. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol. 2000;2:463–5.

  14. 14.

    De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–90.

  15. 15.

    De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518–22.

  16. 16.

    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. Proc Natl Acad Sci USA. 1999;96:6959–63.

  17. 17.

    Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422:438–41.

  18. 18.

    Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, et al. 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;3:325–37.

  19. 19.

    Jacobsen H, Reinhardt D, Brockhaus M, Bur D, Kocyba C, Kurt H, et al. The influence of endoproteolytic processing of familial Alzheimer’s disease presenilin 2 on abeta42 amyloid peptide formation. J Biol Chem. 1999;274:35233–9.

  20. 20.

    Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, et al. 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;274:7615–8.

  21. 21.

    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. 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;2:864–70.

  22. 22.

    Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17:1005–13.

  23. 23.

    Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383:710–3.

  24. 24.

    Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc Natl Acad Sci USA. 2017;114:E476–E485.

  25. 25.

    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.

  26. 26.

    Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995;377:355–8.

  27. 27.

    Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629–39.

  28. 28.

    Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997;387:288–92.

  29. 29.

    Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, et al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA. 1996;93:14940–4.

  30. 30.

    Guo J, Wei J, Liao S, Wang L, Jiang H, Tang B. A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer’s disease. Neurosci Lett. 2010;468:34–37.

  31. 31.

    Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, et al. Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA. 2006;103:18727–32.

  32. 32.

    Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C. Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1997;1:149–59.

  33. 33.

    Ezquerra M, Carnero C, Blesa R, Gelpi JL, Ballesta F, Oliva R. A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures. Neurology. 1999;52:566–70.

  34. 34.

    Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, et al. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer’s disease. Neuroreport. 1998;9:3335–9.

  35. 35.

    Chen F, Gu Y, Hasegawa H, Ruan X, Arawaka S, Fraser P, et al. Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch. J Biol Chem. 2002;277:36521–6.

  36. 36.

    Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31:2261–74.

  37. 37.

    Zhang S, Zhang M, Cai F, Song W. Biological function of Presenilin and its role in AD pathogenesis. Transl Neurodegener. 2013;2:15.

  38. 38.

    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: Off J Soc Neurosci. 2006;26:12081–8.

  39. 39.

    Sato C, Takagi S, Tomita T, Iwatsubo T. TheC-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: Off J Soc Neurosci. 2008;28:6264–71.

  40. 40.

    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: Off J Soc Neurosci. 2010;30:15943–50.

  41. 41.

    Watanabe N, Image I II, Takagi S, Tominaga A, Image Image I, Tomita T, et al. 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;285:19738–46.

  42. 42.

    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;281:27633–42.

  43. 43.

    Cai T, Yonaga M, Tomita T. Activation of gamma-Secretase trimming activity by topological changes of transmembrane domain 1 of presenilin 1. J Neurosci. 2017;37:12272–80.

  44. 44.

    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.

  45. 45.

    Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J, Lee M, et al. Identification of gamma-secretase inhibitor potency determinants on presenilin. J Biol Chem. 2008;283:2927–38.

  46. 46.

    Chen B, Bromley-Brits K, He G, Cai F, Zhang X, Song W. Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer’s disease mouse model. Curr Alzheimer Res. 2010;7:255–61.

  47. 47.

    Koelle MR, Horvitz HR. EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell. 1996;84:115–25.

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Acknowledgements

This work was supported by Canadian Institutes of Health Research (CIHR) Operating Grant CCI-117952,TAD-117948, and MOP-142487to WS and CIHR Operating Grant #122216-2013 to CR. WS was the holder of the Tier 1 Canada Research Chair in Alzheimer’s disease. Sh.Z. was the recipient of the Chinese Scholarship Council award. Si.Z. is supported by UBC 4YF Scholarship. Assistance in C. elegans egg-counting was provided by Mahraz Parvand and Dawson Born.

Author contributions

WS conceived and designed the experiments; ShZ, FC, YW, TB, ZW, SiZ, DH and WS performed the experiments; ShZ, FC, YW, TB, ZW, SiZ, JG, LS, BT, CR and WS analyzed and contributed reagents /materials /analysis tools; ShZ, FC, YW, CR and WS wrote the paper. All authors reviewed the manuscript.

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Author notes

  1. These authors contributed equally: S. Zhang, F. Cai, Y. Wu.

Affiliations

  1. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    • Shuting Zhang
    • , Fang Cai
    • , Zhe Wang
    • , Si Zhang
    •  & Weihong Song
  2. Department of Psychiatry, Graduate Program in Psychiatry, Jining Medical University, Jining, China

    • Yili Wu
  3. Department of Psychology, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

    • Tahereh Bozorgmehr
    •  & Catharine Rankin
  4. Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, 400014, Chongqing, China

    • Daochao Huang
  5. Department of Neurology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    • Jifeng Guo
    • , Lu Shen
    •  & Beisha Tang

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The authors declare that they have no conflict of interest.

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Correspondence to Weihong Song.

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https://doi.org/10.1038/s41380-018-0101-x