Y-Secretase

APP undergoes proteolytic processing by several secretases. First, the bulk of the ectodomain needs to be removed by membrane-bound a- or (3-secretases leading to secreted forms of APP and membrane-bound C-terminal fragments a-CTF or (3-CTF, respectively. Regulated intramembrane proteolysis (RIP) of the (3-CTF by y-secretase occurs only after ectodomain shedding and releases the A(3 pqrtide from the membrane (Fig. 2). 

Dtugs in clinical development that directly target the A(3 pathway are at an early stage. Inhibitors of (3- and y-secretases that can lower the A 3 production have entered clinical phase trials with (3-secretase inhibitors being years behind the development of y-secretase inhibitors. Functional y-secretase inhibitors have been shown to reduce the rate of A 3 formation in vitro and in vivo. The reduction of A 3 monomer levels could prevent oligomer formation and subsequent syn-aptotoxicity. Numerous anti-amyloid approaches to... 

Alzheimer s Disease. Figure 2 A(3 is derived from the APP by the sequential action of proteolytic activities exerted by (3- and y-secretases. APP-CTF is (C99) produced after cleavage of the APP by (3-secretase and represents the substrate of the y-secretase. The yellow box marks membrane embedded amino acid residues of A(3 peptide. Scissors represent the main cleavage sites of (3- and y-secretase, e.g. the e- and y-cleavages at positions 49,46, 42, 40 and 38. 

APP is normally cleaved within the A/1 sequence by an unidentified protease, so-called a-secretase, so that most of the extracellular APP is released in a soluble form into the extracellular fluid (see Checler 1995). When jS-amyloid is formed another protease (jS) splits APP so that the complete A/1 sequence persists at the extracellular end of the remaining membrane and intracellular APP chain. This is then cleaved by anaother protease (y-secretase) to release the jS-amyloid (Fig. 18.5). Potentiation of a-or blockage of jS- and y-secretase could reduce the production of A/1 which becomes insoluble and is precipitated (see Hardy 1997). 

Figure 18.5 Schematic representation of possible cleavage sites of APP by a, and y-secretase and the production of j5-amyloid protein. (I) This shows the disposition of APP molecules in 695, 751 and 770 amino-acid chain lengths. Much of it is extracellular. The /1-amyloid (A/I4) sequence is partly extracellular and partly in the membrane. (II) An enlargement of the /1-amyloid sequence. (Ill) Normal cleavage of APP by a-secretase occurs in the centre of A/I4 sequence to release the extracellular APP while the remaining membrane and intracellular chain is broken down by y-secretase to give two short proteins that are quickly broken down. (IV) In Alzheimer s disease ji rather than a-secretase activity splits off the extracellular APP to leave the full AP4 sequence remaining attached to the residual membrane and intracellular chain. 42/43 amino acid )S-amyloid sequence is then split off by y-secretase activity...

Figure 8.20 (A) Generic chemical structure of the y-secretase inhibitors described by Seiffert et al. (2000). (B) y-Secretase inhibitor incorporating a benzophenone photoaffinity label for crosslinking studies.

The sustained attractiveness of photolabeling is apparent from its prominence in studies of y-secretase, an intramembrane protease that contributes to forming amyloid-p peptides and is a major target in Alzheimer s disease [60-62]. y-Secretase is a complex of at least four different polypeptides, and is difficult to engage with high-resolution structural methods. However, in a case of this kind that involves a known target, immunodetection of proteins can often specify the target of y-secretase inhibitor photoaffinity probes such as 19, and proteomic mass spectrometry is not needed. 

Cyclic sulfamides 326 serve as key intermediates in the synthesis of a series of potent and selective y-secretase inhibitors with potential for the treatment of Alzheimer s disease. 

Neuritic plaques, one of the pathological hallmarks of the disease, are composed of swollen neurites, extracellular deposits of Ap 40-42 peptides, (derived from P- and y-secretase cleavages of APP) and surrounding astrocytes and microglia. Neuritic AP plaques are... 

The functions of these protein and their interactions with each other in the complex and in y-secretase activity are not yet fully defined. PS1 may act as an aspartyl protease itself function as a cofactor critical for the activity of... 

Jankowsky, J. L., Fadale, D. J., Anderson, J. et al. Mutant presenilins specifically elevate the levels of the 42 residue P-amyloid peptide in vivo evidence for augmentation of a 42-specific y-secretase. Hum. Mol. Genet. 13 159-170, 2004. 

Esler, W. P., Kimberly, W. T., Ostaszewski, B. L. et al. Activity-dependent isolation of the presenilin-y-secretase complex reveals nicastrin and a y substrate. Proc. Natl Acad. Sci. USA 14 1-6,2002. 

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