P-Secretase

These must be worthwhile objectives and the recent identification by a number of research groups (see Skovronsky and Lee 2000 for description and details) of P-secretase as the membrane-bound aspartyl protease (RACE), S-site APP cleaving enzyme, paves the way for developing possible chemical inhibitors of its activity for experimental and clinical evaluation, although that remains for the future. 

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... 

Vassar, R., Bennett, B. D., Babu-Khan, S. et al. P-secretase cleavage of Alzheimer s amyloid precusor protein by the transmembrane aspartic protease BACE. Science 286 735-741, 1999. 

Farzan, M., Schnitzler, C. E., Vasilieva, N. et al. BACE2, a P-secretase homolog, cleaves at the (3 site and within the amyloid-P region of the amyloid-P precursor protein. Proc. Natl Acad. Sci. USA 97 9712-9717, 2000. 

Yan, R., Bienkowski, M. J., Shuck, M. E. et al. Membrane-anchored aspartyl protease with Alzheimer s disease P-secretase activity. Nature 402 533-537,1999. 

Yang, L. B., Lindholm, K., Yan, R. et al. Elevated P-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nature Med. 9 3-4, 2003. 

There are three genes believed to be involved in the cutting of the amyloids one gene encodes for the APP while two encode the enzymes P-secretase and y-secretase. 

The axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain subunit of kinesin I. An axonal membrane compartment contains APP, P-secretase, and PSl, and the fast anterograde axonal transport of this compartment is mediated by APP and kinesin I. APP proteolysis in this... 

Steinhilb, M.L., Turner, R.S., Gaut, J.R. (2001) The protease inhibito, MG 132, blocks matu-rationof the amyloid precursor protein Swedish mutant preventing cleavage by P-secretase. J. Biol. Chem., 276, 4476-4484. 

Rockenstein, E., Mante, M., Alford, M., et al. (2005) High P-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-P levels. Implications for the treatment of Alzheimer s disease. J. Biol. Chem., 280, 32957-32967. 

Cole, S.L., Grudzien, A., Manhart, I.O., Kelly, B.L., Oakley, H., Vassar, R. (2005) Statins cause intracellular accumulation of amyloid precursor protein, P-secretase-cleaved fragments, and amyloid P-peptide via an isoprenoid-dependent mechanism. J. Biol. Chem., 280, 18755-18770. 

A relatively small minority of APP molecules enter the p-secretase pathway in which p-secretase cleaves APP and releases a soluble fragment, sAPPp. The C-terminal membrane-bound C99 peptide is then cleaved by y-secretase within the transmembrane domain, and two major isoforms of 40 and 42 amino acid lengths with different C-termini, Ap40 and Ap42, are generated. Based on the amino acid sequence, p-secretase is predicted to be a type I transmembrane protein with the active site on the lumenal side of... 

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