Gamma-secretase: substrates and inhibitors.
The amyloid beta-protein (Abeta) deposited in Alzheimer's disease (AD), the most common form of dementia in the elderly, is a secreted proteolytic product of the amyloid beta-protein precursor (APP). Generation of Abeta from the APP requires two sequential proteolytic events, beta-secretase cleavage to generate the amino terminus, followed by gamma-secretase cleavage to generate the carboxyl terminus. Because this process is a central event in the pathogenesis of AD, gamma-secretase is believed to be an excellent therapeutic target. Gamma-secretase activity has been demonstrated to be membrane-associated, with the cleavage site primarily determined by the location of the substrate with respect to the membrane. It has also been shown that this unusual proteolytic activity not only occurs for APP, but also for proteins involved in morphogenic processes or cell proliferation and differentiation such as Notch and ErbB4. Thus far, all gamma-secretase substrates are involved in some form of nuclear signaling. These recent findings have important implications for the development of pharmacological interventions that target gamma-secretase.
Rochette
Marjorie J
MJ
Department of Neuroscience, Mayo Clinic Jacksonville FL 32224, USA. rochette.marjorie@mayo.edu
Murphy
M Paul
MP
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D066247:Receptor, ErbB-4; D051880:Receptors, Notch; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D051880:Receptors, Notch; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse