Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity

Michael S. Wolfe, Weiming Xia, Beth L. Ostaszewski, Thekla S. Diehl, W. Taylor Kimberly, Dennis J. Selkoe

Research output: Contribution to journalArticlepeer-review

1679 Scopus citations


Accumulation of the amyloid-β protein (Aβ) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Aβ from the β-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive γ-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters γ-secretase activity to increase the production of the highly amyloidogenic Aβ42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces γ-secretase activity, indicating that presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in presenilin-1, Asp 257 (in TM6) and Asp385 (in TM7), substantially reduces Aβ production and increases the amounts of the carboxy-terminal fragments of β-amyloid precursor protein that are the substrates of γ- secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp→Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 → TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp385→Ala mutation still inhibited γ-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and γ-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase, an autoactivated intramembranous aspartyl protease.

Original languageEnglish (US)
Pages (from-to)513-517
Number of pages5
Issue number6727
StatePublished - Apr 8 1999

ASJC Scopus subject areas

  • General


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