A-Secretase

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 8.7 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)...

ADAM 10 activation is necessary for EGCG promotion of nonamyloidogenic (a-secretase cleavage) APP processing. Thus, ADAM 10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in AD [Obregon et al., 2006]. 

Scheme 3.5.1. Amyloid precursor protein (APP) degradation. = a-secretase, y8 = /7-secretase, y = y-secretase, C83 = 83 C-terminal amino acid, C99 = 99 C-terminal amino acids.

Manzamines A, E, F, and Y, 8-hydroxymanzamine A and neo-kauluamine did not show any effect on acetylcholinesterase (AChE) or a-amyloid cleaving enzyme (a-secretase, BACEl) using invitro enzymatic assays. Likewise these compounds did not exhibit any significant ability to protect human neuroblastoma SH-SY5Ycells against oxidative stress-induced cell death [44]. 

Cholesterol has been reported to negatively regulate a-secretase, whereas P- and y-secretase activities are positively regulated by cholesterol (Golde and Eckman,... 

Fig. 1 APP cleavage. The APP protein can be cleaved by three different secretases a, p, or y (panel a). Subsequent to normal a-secretase cleavage, sAPPa is produced and released into the extracellular space and the C83 peptide remains in the ceU membrane (panel b). Subsequent to P-secretase cleavage, sAPPp is produced and released into the extracellular space and the C99 peptide remains in the cell membrane (panel c). Subsequent to p-secretase cleavage, the C99 peptide is abnormally cleaved by y-secretase to yield an Ap peptide and the AICD peptide (panel d). Scale is approximate...

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