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Molecular neurobiology
Aug, 2002;26 (1): 81-95.

Gamma-secretase: substrates and inhibitors.

Marjorie J Rochette, M Paul Murphy
Author Information
  1. Marjorie J Rochette: Department of Neuroscience, Mayo Clinic Jacksonville FL 32224, USA. rochette.marjorie@mayo.edu
PMID: 12392058 DOI: 10.1385/MN:26:1:081

Abstract

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.

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MeSH Term

Alzheimer Disease
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Animals
Aspartic Acid Endopeptidases
Drug Design
Endopeptidases
ErbB Receptors
Humans
Macromolecular Substances
Membrane Proteins
Mice
Mice, Knockout
Nerve Tissue Proteins
Presenilin-1
Presenilin-2
Protease Inhibitors
Protein Processing, Post-Translational
Receptor, ErbB-4
Receptors, Notch
Substrate Specificity

Chemicals

Amyloid beta-Protein Precursor
Macromolecular Substances
Membrane Proteins
Nerve Tissue Proteins
PSEN1 protein, human
PSEN2 protein, human
Presenilin-1
Presenilin-2
Protease Inhibitors
Receptors, Notch
ERBB4 protein, human
ErbB Receptors
Erbb4 protein, mouse
Receptor, ErbB-4
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human
Bace1 protein, mouse
Journal Article Research Support, Non-U.S. Gov't

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