Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein


Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-β(1–42) by proteolytic processing of the amyloid precursor protein (APP)1,2,3,4. Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by α- and β-secretase5 of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by γ-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor6, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Processing of amyloid precursor protein.
Figure 2: Pulse-chase experiment demonstrating similar turnover rates for APP holoprotein in PS1+/+ and PS1−/− cultures.
Figure 3: Assessment of the a, amyloid-β(1–40)-, and b, amyloid-β(1–42)-peptide contents in supernatants (‘Sup’) and cell extracts (‘Cell’) of PS1+/+ and PS1−/− littermate neuronal cultures.


  1. 1

    Sherrington, al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Scheuner, al. Secreted amyloid β-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 Alzheimer's disease. Nat. Med. 2, 864–870 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20, 154–159 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Haass, C. Presenilins: genes for life and death. Neuron 18, 687–690 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Haass, C. & Selkoe, D. J. Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75, 1039–1042 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997).

    CAS  Article  Google Scholar 

  7. 7

    Wong, P. al. Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Shen, al. Skeletal and CNS defects in presenilin-1 deficient mice. Cell 89, 629–639 (1997).

    CAS  Article  Google Scholar 

  9. 9

    De Strooper, al. Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence. EMBO J. 14, 4932–4938 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Tienari, al. Intracellular and secreted Alzheimer β-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. Proc. Natl Acad. Sci. USA 94, 4125–4130 (1997).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Simons, al. Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J. Neurosci. 16, 899–908 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Saftig, al. Amyloidogenic processing of human amyloid precursor protein in hippocampal neurons devoid of cathepsin D. J. Biol. Chem. 44, 27241–27244 (1996).

    Article  Google Scholar 

  13. 13

    Haass, al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325 (1992).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Chyung, A. S. al. Novel β-secretase cleavage of amyloid precursor protein in the endoplasmic reticulum/intermediate compartment of NT2N cells. J. Cell Biol. 138, 671–680 (1997).

    CAS  Article  Google Scholar 

  15. 15

    Citron, al. Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different protease activities. Proc. Natl Acad. Sci. USA 93, 13170–13175 (1996).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Klafki, H. al. The carboxy-terminal termini of β-amyloid peptides 1–40 and 1–42 are generated by distinct γ-secretase activities. J. Biol. Chem. 45, 28655–28659 (1996).

    Article  Google Scholar 

  17. 17

    Hartmann, al. Distinct sites of intracellular production for Alzheimer's disease Aβ40/42-amyloid peptides. Nature Med. 3, 1016–1020 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Weidemann, al. Formation of stable complexes between two Alzheimer's disease gene products: presenilin 2 and β-amyloid precursor protein. Nature Med. 3, 328–332 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Xia, al. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer's disease. Proc. Natl Acad. Sci. USA 94, 8208–8213 (1997).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Doan, al. Protein topology of presenilin 1. Neuron 17, 1023–1030 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Li, X. & Greenwald, I. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17, 1017–1021 (1996).

    Article  Google Scholar 

  22. 22

    Lehmann, S., Chiesa, R. & Harris, D. A. Evidence for a six-transmembrane domain structure of presenilin-1. J. Biol. Chem. 272, 12047–12051 (1997).

    CAS  Article  Google Scholar 

  23. 23

    De Strooper, al. Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer's disease-associated presenilins. J. Biol. Chem. 272, 3590–3598 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Levitan, al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 93, 14940–14944 (1996).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Baumeister, al. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorrhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1, 149–159 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Citron, al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    CAS  Article  Google Scholar 

  27. 27

    Vanderstichele, al. in Progress in Alzheimer's and Parkinson's Diseases (eds Fisher, A., Yoshida, M. & Hanin, I.) (Plenum, New York, in the press).

  28. 28

    Barelli, H. Characterization of new polyclonal antibodies specific for 40- and 42-amino-acids-long amyloid β peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases. Mol. Med. 3, 695–707 (1997).

    CAS  Article  Google Scholar 

  29. 29

    De Strooper, al. Basolateral secretion of amyloid precursor protein in MDCK cells is disturbed by alterations of intracellular pH and by introducing a mutation associated with familial Alzheimer's disease. J. Biol. Chem. 270, 4058–4065 (1995).

    CAS  Article  Google Scholar 

Download references


This work was supported by the FWO-Vlaanderen, the Flemish Action Program for Biotechnology (VLAB), the Flemish Institute for Biotechnology (VIB), the K.U.Leuven, the Human Frontier of Science Program (HFSP), the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. We thank B. Greenberg for antibodies anti-APP1-612 and anti-APPKM595/596, D. Selkoe for R1736 and R1282, and F. Checler for FCA3340, C. Dotti, B. Nelissen and E.Vanmechelen for advice; and S. Tiereliers for technical assistance.

Author information



Corresponding authors

Correspondence to Bart De Strooper or Paul Saftig.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

De Strooper, B., Saftig, P., Craessaerts, K. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing