A peptide known as β-amyloid accumulates in Alzheimer's disease and is thought to contribute to the characteristic and pathologic neurodegeneration. Presenilin (PS) proteins are known to mediate γ-secretase activity, which liberates β-amyloid as a consequence of proteolytic cleavage of the transmembrane amyloid precursor protein; mutated PS proteins have been found in patients with hereditary Alzheimer's disease. Four recent studies have strengthened the case that the PS proteins are, in fact, γ-secretase. Herreman et al. and Zhang et al. show in blastocyst cultures that cells lacking presenilins also lack γ-secretase activity. Esler et al. and Li et al. used transition-state inhibitors of γ-secretase and found that these inhibitors bound directly to presenilin. These results add structure to the urgency with which inhibitors of γ-secretase activity are being sought. — JN
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