γ-Secretase: A Catalyst of Alzheimer Disease and Signal Transduction

Table 1.

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)