Amyloid precursor protein, cleavage

Sisodia, S.S. (1992). -amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. USA 89 6075-6079. 

Amyloid precursor protein (APP) is the precursor of (3-amyloid, the main component of senile plaques found in the brain of Alzheimer patients. The production of (3-amyloid from APP to the cells from abnormal proteolytic cleavage of the amyloid precursor protein. Enzymes involved in this cleavage may be suitable targets for the therapy of Alzheimer s disease. 

Most cases of AzD show cerebrovascular amyloid deposits and the amyloid protein of senile plaques is the same as that found in blood vessels. It is referred to as )S-amyloid protein and is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP, which is a transmembrane protein and although its precise function is not clear, it is widely distributed and APP knock-out mice show reduced motor function. Normally so-called short 40 amino-acid-soluble derivatives of APP are produced by proteolytic cleavage of APP within the j] (A4) amino-acid sequence but APP can also be cleaved... 

A universal postmortem hallmark of Alzheimer s disease (AD) is the presence of amyloid plaques in the brain. These plaques are mainly composed of a 39 to 42 amino acid peptide, referred to as A0 peptide, that is excised from a precursor protein, amyloid precursor protein (APP), by the sequential action of two proteases (Olsen et al., 2001). The first of the two cleavages of APP occurs at a site within the APP protein that is termed the P-site, and BACE has been clearly determined to be the enzyme responsible for this cleavage event. A small portion of the AD patient... 

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., et al. (1999). Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BAGE. Science 286, 735—741. 

Vassar, R., Bennet, B.D., Babu-Khan, S., et al. (1999) P-Secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286, 735-741. 

De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., et al. (1998) Deficiency of prese-nUin-l inhibits the normal cleavage of amyloid precursor protein. Nature, 391,387-390. 

Zhao, G., Mao, G., Tan, J., et al. (2004) Identification of a new presenilin-dependent -cleavage site within the transmembrane domain of amyloid precursor protein. J. Biol. Chem., 279, 50647-50650. 

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. 

Irizarry, M.C., Deng, A., Lleo, A., et al. (2004) ApoUpoprotein E modulates gamma-secre-tase cleavage of the amyloid precursor protein. J. Neurochem., 90, 1132-1143. 

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, File J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G Citron M. (1999) Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286 735-741. 

Strong evidence suggests that the main constituent of the plaque, P-amyloid peptide (AP), exerts a prominent role in the cause, initiation and progression of AD. Thus AD appears to arise from the abnormal deposition of a protein. Ap is derived from proteolytic cleavage of amyloid precursor protein (APP), an integral membrane protein. APP is cleaved by the sequential actions of three unique proteases, called a-, p-, and y-secretases. Each secretase cleaves at a unique site (see figure 8.7). 

Figure 8.7 Top Sequence of Api 3 and sites of secretase cleavage. y-Secretase has low specificity, cleaving the amyloid precursor protein (APP) anywhere between residues 39 to 43 of Ap. The transmembrane portion of APP is indicated. Bottom processing of amyloid precursor protein (APP) (A) Normal cleavage within AP region by a-secretase (B) pathogenic cleavage of APP by P- and y-secretase, liberating Ap, which can become incorporated into growing plaques. (Note AP = P-Amyloid Peptide)...

Figure 30-34 Cleavage of the amyloid precursor protein APP with liberation of amyloid A 3 protein. The proteins are represented as sticks (not to scale) but in reality contain both intracellular and extracellular globular domains.

Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart J, Zeng J, Mori T, Arendash GW, Shytle D, Town T, Tan J. 2006. ADAM10 activation is required for green tea (—)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 281 16419-16427. 

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