Abstract
In the nonamyloidogenic processing pathway the Alzheimers amyloid precursor protein (APP) is proteolytically cleaved by α-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid β domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPPα) released by the action of α-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that α-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of α-secretase. APP is constitutively cleaved by α-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the α-secretase cleavage of APP is up-regulated. The constitutive α- secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi. The beneficial action of cholinesterase inhibitors may in part be due to activation of muscarinic receptors, resulting in an up-regulation of α-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the α- secretase cleavage of APP both precludes the deposition of the amyloid β peptide and releases the neuroprotective sAPPα, pharmacological up-regulation of α-secretase may provide alternative therapeutic approaches for Alzheimers disease.
Keywords: alpha secretase, lys16-leu17, sappalpha
Current Medicinal Chemistry
Title: The Search for α-Secretase and its Potential as a Therapeutic Approach to Alzheimers Disease
Volume: 9 Issue: 11
Author(s): N. M. Hooper and A. J. Turner
Affiliation:
Keywords: alpha secretase, lys16-leu17, sappalpha
Abstract: In the nonamyloidogenic processing pathway the Alzheimers amyloid precursor protein (APP) is proteolytically cleaved by α-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid β domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPPα) released by the action of α-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that α-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of α-secretase. APP is constitutively cleaved by α-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the α-secretase cleavage of APP is up-regulated. The constitutive α- secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi. The beneficial action of cholinesterase inhibitors may in part be due to activation of muscarinic receptors, resulting in an up-regulation of α-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the α- secretase cleavage of APP both precludes the deposition of the amyloid β peptide and releases the neuroprotective sAPPα, pharmacological up-regulation of α-secretase may provide alternative therapeutic approaches for Alzheimers disease.
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Cite this article as:
Hooper M. N. and Turner J. A., The Search for α-Secretase and its Potential as a Therapeutic Approach to Alzheimers Disease, Current Medicinal Chemistry 2002; 9 (11) . https://dx.doi.org/10.2174/0929867023370121
DOI https://dx.doi.org/10.2174/0929867023370121 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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