Evidence that Presenilins Contain the Active Site of γ-Secretase
Experimental approach | Observation | Reference |
---|---|---|
Knockout mice | γ-secretase-mediated cleavage of APP is reduced in PS1 knockout cells | (28, 29) |
PS1 and PS2 double-knockout cells fail to produce Aβ | (30, 31) | |
Site-directed mutagenesis | Substitutions of aspartate residues in PS1 transmembrane regions reduce Aβ production | (32) |
Genetics of early-onset familial AD | Mutations in presenilin-encoding genes increase production of Aβ42 and precipitate AD | (22, 23) |
Sequence homology | Presenilins show limited homology with a unique family of aspartyl proteases (TFPP) | (36) |
In vitro enzymology | Transition-state analogs that inhibit aspartyl proteases bind directly to presenilins | (16, 17, 33) |