Relationship between presenilinase and gamma-secretase.
Genetic and neuropathological studies suggest that processing of amyloid precursor protein (APP) to yield amyloid beta-protein (Abeta) 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 gamma-secretase activity that produces Abeta. Compelling evidence for presenilin (PS) possessing gamma-secretase activity includes a lack of Abeta 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 gamma-secretase. In vitro studies have shown a binding of transition-state analog gamma-secretase inhibitors to PS N-terminal fragment (NTF) and C-terminal fragment (CTF), the functional form of PS detected in the high-molecular-weight gamma-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 gamma-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 gamma-secretase inhibitors can block presenilinase activity in vivo and in vitro, the potency of inhibitors blocking presenilinase and gamma-secretase are not correlated. Lack of presenilinase inhibition by several potent gamma-secretase inhibitors suggests that these two protease activities are pharmacologically distinct.
Xia
Weiming
W
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes for Medicine, Boston, Massachusetts 02115, USA. wxia@rics.bwh.harvard.edu
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C475285:presenilinase, human; C509280:BACE1 protein, human