More Clues in the Case, but γ-Secretase Remains at Large

In the search for the elusive γ-secretase that cleaves β-amyloid precursor protein (APP), much attention has been paid to the protein Notch, which is critical in developmental pathways and has recently been found to be important in immune function. Like APP, Notch is a membrane-spanning protein that appears to undergo proteolytic cleavage within the plasma membrane. Notch came to the attention of the Alzheimer's research community when it was discovered that homologues of the presenilins-critical for γ-secretase activity-were involved in the developmental signaling pathways of Notch. The question was posed as to whether γ-secretase is also involved in the cleavage of Notch. The relationship between the presenilins, Notch, and γ-secretase is explored in four papers in the April 8 issue of Nature.

Three of the papers focus on the relationship between presenilins and Notch, and two of these cover much of the same ground, coming to similar conclusions. Both Mark Fortini and his colleagues, and Gary Struhl and Iva Greenwald analyze Drosophila development with, and without, loss-of-function mutations in the presenilin gene. In the presence of presenilin mutations, each group finds lethal phenotypic changes related to Notch pathways. Fortini and colleagues further examine the resultant Notch species and conclude that the absence of presenilin prevents a crucial proteolytic cleavage event. Struhl and Greenwald are able to demonstrate that in the absence of presenilin, Notch is not capable of reaching the nucleus.

Working in presenilin-deficient murine fibroblasts, Bart De Strooper, Raphael Kopan, and their colleagues show a reduction in proteolysis of Notch in the absence of presenilin. They go on to identify the specific step in the Notch pathway that is affected by presenilin deficiency: the release of the Notch intracellular domain from the membrane. Finally, they construct a γ-secretase inhibitor from APP and demonstrate that it inhibits this same step in Notch processing.

Michael Wolfe, Dennis Selkoe, and colleagues add fuel to the argument that the presenilins are, in fact, γ-secretase. They demonstrate that two transmembrane aspartate residues in presenilin-1 are essential for APP cleavage and suggest that if the presenilins are not γ-secretase, they at least facilitate the activity of the protease involved in intramembrane cleavage. This view is echoed by Struhl and Greenwald and by De Strooper, Kopan, and colleagues.

A note of caution comes from John Hardy and Alain Israel in a News and Views article in the same issue. They opine that work to date, including these most recent results, do not show conclusively whether the presenilins act on the cleavage process or whether they are involved in trafficking upstream of the proteolytic events (as Fortini and colleagues suggest). Hardy and Israel also raise another critical point: Notch is not just a developmental player, but has a role in the formation of blood cells. Therefore, any targeting of γ-secretase to combat Alzheimer's disease may have unwanted immunosuppressive effects.—Hakon Heimer

For further discussion, including Dennis Selkoe's response to points raised in the News and Views article, visit our interactive panel discussion on these papers.

Comments

  1. Unquestionably this is a core paper for AD study.

    View all comments by Hiroshi Mori

  2. A turning point in the molecular history of neurodegenerative disorders.

    View all comments by Andre Delacourte

  3. Unquestionably this is a core paper for AD study.

    View all comments by Hiroshi Mori

  4. The abstract states: 'Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.' A potentially important cautionary note.

    View all comments by Paul Coleman

  5. [Also] Unquestionably this is a core paper for AD study.

    View all comments by Hiroshi Mori

  6. Unquestionably this is a core paper for AD study.

    View all comments by Hiroshi Mori

  7. A turning point in the molecular history of neurodegenerative disorders.

    View all comments by Andre Delacourte

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References

Other Citations

  1. panel discussion

Further Reading

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Primary Papers

  1. Hardy J, Israël A. Alzheimer's disease. In search of gamma-secretase. Nature. 1999 Apr 8;398(6727):466-7. PubMed.
  2. 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 Apr 8;398(6727):513-7. PubMed.
  3. 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 Apr 8;398(6727):518-22. PubMed.
  4. Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 1999 Apr 8;398(6727):522-5. PubMed.
  5. Ye Y, Lukinova N, Fortini ME. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature. 1999 Apr 8;398(6727):525-9. PubMed.

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