Genetic and neuropathological studies suggest that processing of amyloid precursor protein (APP) to yield amyloid β-protein (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). One of the current therapeutic efforts for AD is directed towards blocking the γ-secretase activity that produces Aβ. Compelling evidence for presenilin (PS) possessing γ-secretase activity includes a lack of Aβ production in PS knockout neurons and in cultured cells carrying a dominant negative mutation at either of two critical aspartate residues in PS, which may constitute the active site of γ-secretase. In vitro studies have shown a binding of transition-state analog γ-secretase inhibitors to PS N-terminal fragment (NTF) and C-terminal fragment (CTF), the functional form of PS detected in the high-molecular-weight γ-secretase complex that also contains nicastrin, Aph-1 and PEN-2. Conversion of full-length PS into functional NTF and CTF is mediated by an unknown protease activity named presenilinase. Endoproteolysis of PS into NTF/CTF by presenilinase also requires two critical aspartate residues, suggesting that full-length PS may undergo autoproteolysis and PS itself is presenilinase. Similar to γ-secretase, presenilinase seems to be an aspartyl protease, as aspartyl protease inhibitor pepstatin A is the most potent inhibitor toward presenilinase among different classes of protease inhibitors. While several well-characterized γ-secretase inhibitors can block presenilinase activity in vivo and in vitro, the potency of inhibitors blocking presenilinase and γ-secretase are not correlated. Lack of presenilinase inhibition by several potent γ-secretase inhibitors suggests that these two protease activities are pharmacologically distinct.
ASJC Scopus subject areas
- Drug Discovery