Gamma-secretase: substrates and inhibitors |
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Authors: | Rochette Marjorie J Murphy M Paul |
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Institution: | (1) Department of Neuroscience, Mayo Clinic Jacksonville, Birdsall Medical Research Building, 3rd Floor, 4500 San Pablo Road, 32224 Jacksonville, FL |
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Abstract: | The amyloid β-protein (Aβ) deposited in Alzheimer’s disease (AD), the most common form of dementia in the elderly, is a secreted
proteolytic product of the amyloid β-protein precursor (APP). Generation of Aβ from the APP requires two sequential proteolytic
events, β-secretase cleavage to generate the amino terminus, followed by γ-secretase cleavage to generate the carboxyl terminus.
Because this process is a central event in the pathogenesis of AD, γ-secretase is believed to be an excellent therapeutic
target. γ-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 γ-secretase substrates are involved in some form of nuclear signaling. These recent
findings have important implications for the development of pharmacological interventions that target γ-secretase. |
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Keywords: | Alzheimer’ s disease γ -secretase presenilin amyloid β -peptide amyloid β -protein precursor Notch ErbB4 γ -secretase inhibitors |
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