21 Jun 2001

The γ-secretase enzyme activity is a therapeutic target in Alzheimer's disease. Yet its promise of lowering the Aβ42 burden has been under a cloud since 1999, when Bart De Strooper and other scientists found that the enzyme also cleaves Notch, a cell surface receptor mediating cell fate decisions during development as well as in adult self-renewing cells.

In the June 19 PNAS, researchers in Raphael Kopan's lab at Washington University School of Medicine in St. Louis and others report that an experimental γ-secretase inhibitor developed by coauthor Michael Wolfe, now at Brigham and Women's Hospital in Boston, Massachusetts, impairs the maturation of thymocytes, deepening earlier concerns that this approach might cause immunodeficiency.

The scientists cultured fetal thymic lobes in 50 micromolar of the inhibitor Cpd.11 and found T cell development arrested at two steps. First, most immature thymocytes failed to progress from the early CD4/CD8 double-negative stage to the intermediate CD4/CD8 double-positive stage. Second, when applied to CD4/CD8 double-positive thymocytes, the inhibitor blocked the maturation of single-positive CD8 cells (the cytotoxic T cells.) Each lobe also contained 40 percent fewer cells. Taken together, pharmacological γ-secretase inhibition produced similar results to genetic manipulation of notch signaling.

The significance of thymocyte development in the elderly is unclear. Conventional wisdom in immunology holds that most thymocyte maturation occurs in children, yet recent studies in transplant patients and other systems suggest that significant numbers of new T cells are being generated during adulthood, possibly at sites other than the thymus. Moreover, Notch has been implicated in the generation of red blood cells, the myeloid lineage, and hematopoietic progenitors.

γ-secretase remains a target, says Kopan, especially if inhibitors can be found that are more potent against APP than against notch. Companies developing γ-secretase inhibitors could use this assay to weed out candidate drugs preclinically, or the FDA could require such testing, he adds.

Indeed, agrees Steven Paul of Eli Lilly and Company, industry scientists have long known about this potential complication and are including such testing in their research. A key question at this stage is whether the therapeutic window between minimal interference with notch on the one hand and clinically effective Aβ42 reduction on the other hand is big enough for any of the current drugs to be safe and effective. γ-secretase programs are still being actively pursued at Lilly, Merck, Bristol-Myers Squibb and elsewhere.—Gabrielle Strobel

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