Please note these web pages are part of an assignment for a graduate course in Advanced Biochemistry and Molecular Biology (BCMB8010) at the University of Georgia. Questions should be directed to Crystal Jackson.

BODY 4 OF 4

Figure 5

When beta-secretase inhibited, no beta amyloid fragment and no plaque deposits are formed. Inhibition of BACE may not be the answer to regulation of beta amyloid plaque formation, and, in turn, the regulation of AD pathogenesis, because it may inhibit important physiological functions of BACE with other substrates [2]. As an alternative, recent studies have shown that regulating the subcellular localization of BACE may control beta-C-fragment formation and thus affect the proliferation of AD [44].

Other Secretases
alpha-secretase:
Alpha secretase destroys the beta amyloid fragment by cleaving on C-terminal side of residue 16 of beta amyloid sequence in APP, yielding an 83 residue C-terminal fragment (C83) and sAPP alpha [45]. Subsequent cleavage of the C83 by gamma-secretase yields a short peptide with a C-terminus known as p3. Alpha -secretase is inactive in the Golgi and active at the plasma membrane [46]. It may be more than one enzyme because it has both constitutive and regulated activity. Regulated activity puts alpha -secretase cleavage under the control of protein kinase C (PKC) [16], which is regulated by muscarinic acetylcholine (ACh) receptor [47].
ADAM ( a disintegrin and metalloprotease) family may hold the identity of the alpha -secretase [2,48,49,46]. The two contenders are TACE ( tumor necrosis factor- alpha (TNF alpha)-converting enzyme or ADAM-17) and ADAM-10 [2]. Cells deficient in TACE still have alpha -secretase activity and, therefore, TACE may be involved in regulated PKC-dependent alpha -secretion. ADAM-10 has a zinc binding site, and phorbol ester-inducible alpha -secretase cleavage activity [46], which may not affect the PKC-dependent secretase activity [48] of TACE. Taking into consideration the information previously stated, both ADAM-10 and ADAM-17or TACE maybe alpha -secretases. Because of the possibility of several proteases contributing in alpha -secretase activity, it may be difficult to pharmacologically regulate APP processing via the alpha-secretase pathway. Therefore, drug inhibition studies are targeted to beta- and gamma -secretases.

g-secretase:
The final step in beta amyloid production is the cleavage of an APP C99 fragment by gamma -secretase [2]. Integral membrane proteins called presenilin (PS) 1 and 2 are candidate gamma-secretases. They have eight putative transmembrane domains encoded by genes on chromosomes 14 and 1 [50]. PS1 and PS2 knockouts yield no gamma -secretase activity [51]
Mutations in PS1's have been shown to cause familial AD and to increase the presence of long Abeta species [52,53]. Furthermore, gamma-secretase processing occurs in the Golgi and PS's are localized in such subcellular compartments [17]. Affinity-labeling of PS subunits by gamma -secretase inhibitors [50,51] provides further evidence supporting the candidacy of PS's as gamma -secretases [54,55]. In contrast, however, PS may simply be a regulatory subunit of gamma -secretase or it may be involved in protein-trafficking to gamma-secretase [2,56].

Possibly, like beta-secretase, gamma -secretase has activity other than the processing APP. Therefore, drug inhibition of gamma -secretase would affect AD-unrelated processes [57].
For example, gamma -secretase is involved in Notch processing. Notch plays a role in neuronal differentiation regulation, spermatogenesis, oogenesis and myogenesis [58]. It may be possible, however, for gamma-secretase to be altered in such a way that A production is decreased, while Notch processing and the signaling pathway are unaffected.

In Summary, See Figure 6 Below

Figure 6.
Alpha secretase cleavage of APP yields a C83 fragment and sAPP alpha. Subsequent cleavage of C83 by gamma-secretase yields a p3 fragment. beta-secretase cleavage of APP yields a C99 fragment and sAPPbeta. Subsequent cleavage of C99 by gamma-secretase yields beta amyloid and, hence, neurotoxicity.