The Search for agr-Secretase and its Potential as a Therapeutic Approach to Alzheimer's Disease

Authors: Hooper N.M.; Turner A.J.

Source: Current Medicinal Chemistry, Volume 9, Number 11, June 2002 , pp. 1107-1119(13)

Publisher: Bentham Science Publishers

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Abstract:

In the nonamyloidogenic processing pathway the Alzheimer's amyloid precursor protein (APP) is proteolytically cleaved by agr-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid bgr domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPPagr) released by the action of agr-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that agr-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 agr-secretase. APP is constitutively cleaved by agr-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the agr-secretase cleavage of APP is up-regulated. The constitutive agr- 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 agr-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the agr- secretase cleavage of APP both precludes the deposition of the amyloid bgr peptide and releases the neuroprotective sAPPagr, pharmacological up-regulation of agr-secretase may provide alternative therapeutic approaches for Alzheimer's disease.

Keywords: alpha secretase; lys16-leu17; sappalpha

Language: English

Document Type: Review article

DOI: 10.2174/0929867023370121

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