Presenilin 1: gamma-secretase or a gamma-secretase Cofactor

Figure. 1. Structure of PS1 and chemical inhibitors. PS1 plays a role in gamma-secretase cleavage of APP. BACE/beta-secretase (blue) cleaves APP after Met671, creating a membrane-retained C-terminal fragment. This fragment can then be cleaved by gamma-secretase (purple) within the hydrophobic transmembrane domain to release A beta. [Inset: Chemical structures of the gamma-secretase inhibitor derivatives, L-852,505 and L-852,646 (both are photoreactive/biotinylated analogues of L-685,458).2] L-852,505 and L-852,646 covalently label PS1-CTF and PS1-NTF, respectively, thus suggesting that the active site of ?-secretase may be shared between the two subunits of PS1.

Deposition of amyloid beta (A beta) peptides within extracellular plaques in the brains of Alzheimer’s Disease (AD) patients occurs following amyloid precursor protein (APP) cleavage by various proteases. The three proteases involved in processing APP include: alpha-, beta- and gamma-secretase (see references 1-4 for reviews). APP is cleaved at the N-terminus after Met671 by beta-secretase. The membrane-retained C-terminal fragment can then be further cleaved by gamma-secretase within the hydrophobic transmembrane domain, thus releasing A beta (see figure 1).

Identification and characterization of the beta- and gamma-secretases involved in APP cleavage and A beta generation have been important areas of focus within AD research. Although several candidates have been suggested for beta-secretase, BACE is the only one identified having complete beta-secretase activity.5 The gamma-secretase has not been definitively identified yet. Numerous studies, however, have suggested that gamma-secretase and presenilin-1 (PS1) are closely linked.6-14 PS1 either functions as gamma-secretase itself or as a required cofactor within the gamma-secretase protein complex.

PS1 is a target for various gamma-secretase inhibitors.7-9,15,16 For example, two different photoaffinity analogues of L-685,458 (a potent gamma-secretase inhibitor) covalently label PS1, thus suggesting that the active site of gamma-secretase may be shared between the two subunits of PS1 (see figure 1).7 PS1 is proteolytically cleaved to yield a non-covalent heterodimer involving an N-terminal fragment (NTF) and a C-terminal fragment (CTF). The photoactivated gamma-secretase inhibitors, L-852,505 and L-852,646, covalently label PS1-CTF and PS1-NTF, respectively. By contrast, these inhibitors do not label the intact form of PS1. As a result, intact PS1 may require activation in order to function as a protease.

Although PS1 appears to contain the active site of gamma-secretase, it does not preclude the possibility that PS1 may serve as a cofactor within a gamma-secretase complex. In the study by Seiffert et al.,15 radiolabeled gamma-secretase inhibitors bind cell membranes and a benzophenone analog specifically cross-links three major membrane polypeptides. The PS1 fragments, PS1-NTF and PS1-CTF, are two of the cross-linked polypeptides.15 Detergent solubilization and partial characterization of gamma-secretase suggest that gamma-secretase activity is catalyzed by a PS1-containing macromolecular complex.8 PS1 may also facilitate the presentation of APP fragments for gamma-secretase through a direct interaction. Inhibition of APP C-terminal cleavage with the protease inhibitor N-acetyl-leucyl-norleucinal and the lysosomotropic agent NH4Cl results in the accumulation of APP fragments.16 Immunoprecipitation studies demonstrate that a major portion of these fragments can be co-immunoprecipitated with PS1.16 Collectively, these results implicate PS1 functioning as a major component (i.e. cofactor) within a gamma-secretase complex.

PS1, whether it is gamma-secretase itself or a cofactor within a ?-secretase protein complex, may prove to be a potential therapeutic target for AD. Numerous mutations have been described within the PS1 gene that can promote the development of familial AD (FAD).13,17-19 Examples of mutations in PS1 have been specifically associated with an increased production of the A beta 42 peptide and with facilitation of neuronal apoptosis by destabilizing beta-catenin (i.e. part of the PS protein signaling complex), thus predisposing individuals to early onset FAD.17,20-28 An increase in the degradation of beta-catenin has been noted in the brains of AD patients with PS1 mutations.28 Further research of PS1 physiological functions and its specific role(s) in the pathogenesis of AD (whether as gamma-secretase itself or as a cofactor) will lead to the development of specific drugs for the treatment of AD.

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