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Physiology 23: 194-204, 2008; doi:10.1152/physiol.00009.2008
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Physiology, Vol. 23, No. 4, 194-204, August 2008
© 2008 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Presenilins: Members of the {gamma}-Secretase Quartets, But Part-Time Soloists Too

Tomoko Wakabayashi1,2 and Bart De Strooper1,2

1 Department for Developmental and Molecular Genetics, VIB, Leuven, and
2 Center for Human Genetics, KULeuven, Leuven, Bart.destrooper{at}med.kuleuven.be


   Abstract
 
The presenilins in combination with other proteins generate different {gamma}-secretases, which are involved in the regulated intramembrane proteolysis of a variety of proteins. Understanding the specificity and regulation of these proteases will potentially lead to novel therapeutics for Alzheimer’s disease and cancer. Presenilins appear also to exert additional functions outside of the {gamma}-secretase quartets, which needs further investigation.


   Introduction
Top
 Introduction
Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 
Until 1998, {gamma}-secretase was a generic name for a proteolytic activity that, in combination with β-secretase, was able to cleave the amyloid beta (Aβ) peptide from the amyloid precursor protein (APP) (24). The Aβ peptide is crucially involved in the pathogenesis of Alzheimer’s disease (AD), and interest in these enzymatic activities was largely restricted to this field. The finding that genetic inactivation of presenilin 1 led to almost complete loss of Aβ peptide generation in neurons provided the first clear evidence that presenilins constitute an essential part of {gamma}-secretase activity (11) and was an important step toward the progressive molecular dissection of the {gamma}-secretase complex (FIGURE 1Go). It became rapidly clear that presenilin/{gamma}-secretase was also involved in the proteolysis of Notch (10, 81, 97), explaining the dominant Notch phenotype in presenilin loss of function animals (48, 75, 94).


Figure 1
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  		FIGURE 1. The {gamma}-secretase complex
{gamma}-Secretase is a highly hydrophobic complex composed of four integral membrane proteins: presenilin, nicastrin, Aph-1, and Pen-2. Presenilin 1 and presenilin 2, and Aph-1a and Aph-1b are encoded by different genes, and all subunits can combine to generate at least four different complexes. Alternative splicing of these genes adds further complexity. Presenilin provides the active site with two catalytic aspartates located in transmembrane domains (TM) 6 and 7 (indicated as stars). Nicastrin and Aph-1 first form a stable subcomplex, followed by incorporation of presenilin and Pen-2 in the early secretory compartment. Once all four components assemble, presenilin undergoes endoproteolysis by unknown "presenilinase" activity within the large intracellular loop between TM6 and TM7 (indicated by an arrow), and the aminoterminal fragment (NTF) and the carboxyterminal fragment (CTF) remain noncovalently bound. Only fully assembled complexes reach the cell surface and endocytic compartments.

 
In 1999, the concept of intramembrane cleaving proteases (i-Clips) and of regulated intramembrane proteolysis (RIP) became established (4, 92), demonstrating that intramembrane cleavage of proteins is a general and biologically widespread mechanism. A large family of such proteases is currently known, covering three major functional classes of catalysis: the aspartyl proteases represented by the presenilins and the signal peptide peptidase (SPP) family or presenilin homologs (PSH) (23, 62, 55, 89), the metallo-proteases represented by the site-2-proteases (63), and finally the serine proteases represented by the rhomboids (47, 85) (FIGURE 2Go). Although these proteases have widely divergent structures and functions, they all bury their catalytic site deeply in their large hydrophobic cores. Most recently, crystal structures of some i-Clips have been published, providing a first glimpse on how these proteins are capable of catching water and performing hydrolysis in the lipid environment of the membrane (2, 16, 88, 95). The field of i-Clip biology is evolving with a fascinating speed, and the novel insights are touching a broad area of biology and physiology. We focus in the current review on the presenilins.


Figure 2
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  		FIGURE 2. Membrane topologies and conserved motifs for i-CLiP family proteins
Schematic structures of representatives of the three i-CLiP family proteins, presenilin and SPP/SPPLs (aspartyl protease), site-2 protease and SpolVFB (metalloprotease), and rhomboid and GlpG (serine protease). The locations of putative catalytic residues of each protease are indicated in white letters in black circle. Presenilin and SPP/SPPLs are aspartyl proteases that share similar but opposite membrane topology. Sequences surrounding the active site aspartates (YD in TM6 and GxGD in TM7) are highly conserved among presenilin and SPP family proteins, as well as PAL motif located in TM9, which is indispensable for enzymatic activity of the {gamma}-secretase complex (indicated in the box).

 

   Presenilins are Part of an Oligomeric Complex
Top
 Introduction
 Presenilins are Part of...
The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 
Presenilins are part of a larger {gamma}-secretase complex. Estimates of the molecular weight (Mr) of this complex have been highly divergent (250 to >2,000 kDa). Gel filtration experiments (50) probably overestimated the actual size of the complex due to incomplete solubilization of the membranes. Blue Native gel electrophoresis (13, 18) or glycerol gradients indicate Mr ranges varying between 100 and 900 kDa (5, 15, 99). Different methodologies (including the use of different detergents) explain these discrepancies, but likely the heterogeneity also reflects weak or transient interactions of proteins with the complex, since such interactions likely regulate its trafficking and activity.

Presenilin (FIGURE 1Go) is a nine-membrane domain protein (42, 29, 78) and is under physiological conditions cleaved in an aminoterminal (~27- to 30-kDa NTF) and a carboxyterminal fragment (~16- to 18-kDa CTF). The catalytic site of presenilin consists of two critical aspartyl residues, each located on one of these noncovalently bound fragments (93). They are together with the surrounding amino acids (YD and GLGD) (79), completely conserved in the presenilins and their cousins (FIGURE 2Go).

The presenilin holoprotein, in contrast to the presenilin fragments, is detected in lower weight fractions (50–150 kDa), indicating that the holoprotein remains isolated until incorporated into the complex. The minimum Mr estimate of this complex is 250 kDa and equals more or less the sum of the Mrs of presenilin, nicastrin, Aph-1, and Pen-2 (FIGURE 1Go), which are the four proteins that are necessary and sufficient to restore {gamma}-secretase activity (Refs. 14, 37, 83; reviewed in Ref. 8). The stoichiometry of the {gamma}-secretase components is likely 1:1:1:1 (67), although the higher Mr estimates of the complex in some assays (see above) are compatible with the possibility that also larger multimers are formed or that additional proteins are incorporated into the complex. Some evidence indeed suggests that presenilin can form homodimers (27, 70). It must be said that most of the experiments studying assembly and stoichiometry of the complex have used overexpressed and tagged versions of the subunits, which is a considerable source of artifacts and might bias our current view of the complex.

Nicastrin was co-purified using antibodies against presenilin (100). It is an evolutionarily conserved, 130-kDa type I integral membrane protein that is highly glycosylated. Nicastrin was also identified as Aph-2 (anterior pharynx defective) in a screen for genetic interactors of the GLP-1 pathway (the Notch pathway in C. elegans) (21).

The two other {gamma}-secretase components, Aph-1 and Pen-2, were identified in similar genetic screens (19, 22). Aph-1 has likely a seven TM structure with the COOH terminus located in the cytoplasm (17). Pen-2 displays a hairpin-like structure with two transmembrane domains and both termini located at the luminal side (7) (FIGURE 1Go).

The four proteins co-migrate in non-denaturing electrophoresis gels, and downregulation of any of the four proteins using either RNA interference (RNAi) or classical genetic knockout results in retention of the other components in the endoplasmic reticulum or their rapid degradation and loss of {gamma}-secretase function (8). It is somewhat puzzling why presenilin needs three other proteins to exert its proteolytic function. The presenilin homologs (FIGURE 2Go) have a similar putative catalytic site as presenilin and can be blocked by similar types of protease inhibitors (89, 90), but they can perform their activity, as far as we know, as single or homodimeric proteins (57, 61, 89).

Nicastrin, with its long ectodomain, has been suggested to act as a "gate keeper," restricting access of substrates to the complex. Shah et al. (74) showed that the extracellular domain of nicastrin binds specifically to the amino-terminal residue of membrane-tethered substrate fragments. This domain of nicastrin is reminiscent of aminopeptidase structures, and the carboxylate side chain of a conserved glutamate residue (E333) in this structure was suggested to be crucial for the nicastrin-substrate interaction. This domain also encompasses a stretch of amino acid residues (DYIGS) previously shown to modulate APP processing (100). Although very attractive, the hypothesis has not been further corroborated, and recent work in our laboratory has shown that E333 substitution interferes with {gamma}-secretase assembly. This on its own does not contradict the hypothesis, but the small amount of complexes that are still generated appeared to be on a per mol basis as active as the wild-type complex in reconstituted nicastrin knockout cell lines in vitro (6a). Further work is needed to decipher the exact contribution of nicastrin to {gamma}-secretase activity.


   The Presenilins in Regulated Intramembrane Proteolysis
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 
Presenilin/{gamma}-secretase cleaves with remarkable relaxed sequence specificity transmembrane domains of many proteins (Table 1Go). The only requirements are apparently a type I conformation of the transmembrane domain (aminoterminus oriented to the extra-cellular side of the membrane) and a short (<50 AA) ectodomain (51, 80). Bulky ectodomains of 200 and more amino acid residues prevent {gamma}-secretase cleavage and are usually removed by membrane bound (metallo)-proteases or "sheddases" at the cell surface (FIGURE 3Go). This first cleavage can be triggered by ligand binding, as is the case for Notch, whereas for other substrates, e.g., APP, shedding is largely constitutive. {gamma}-Secretase cleavage occurs at different positions in the membrane domain of its substrates, resulting in the generation of a series of small peptides (Aβ, Nβ, CD-44β, etc.; see Table 1Go and FIGURE 3Go), which are secreted at the extracellular side of the membrane. The best studied example is Aβ, and the heterogeneity of its carboxyterminus is directly relevant for the pathogenesis of AD as we will explain below. The physiological significance of Aβ and the other secreted peptides remains largely unexplored, although Aβ might be involved in the modulation of synaptic transmission (30, 34).


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  		Table 1. {gamma}-Secretase substrates
 

Figure 3
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  		FIGURE 3. Successive cleavage of {gamma}-secretase substrates
Ectodomain shedding of type I membrane substrates is executed by a membrane-tethered metalloprotease generally called "sheddase," including ADAM proteases and BACE (β-secretase). Cleaved ectodomain is released, and the membrane stub becomes a substrate for further cleavage by {gamma}-secretase. The stub moves into the inner barrel of the {gamma}-secretase complex followed by proteolysis in the transmembrane domain. Several substrates have been shown to be cleaved at least at two positions, namely {varepsilon} (S3) and {gamma} (S4) cleavage (white arrows). Several models propose consecutive cleavages from {varepsilon} (S3) to {gamma} (S4) sites of the substrate (black arrow). {varepsilon}-Cleavage releases the intracellular domain (ICD) into the cytoplasm, and some of the ICDs have been shown to translocate to the nucleus, whereas {gamma}-cleavage secretes NH2-terminal peptides, such as Aβ, from the membrane.

 
The polypeptides released at the intracellular side are by many authors considered the business ends of the process (Table 1Go). Based on the canonical model for this type of signaling, i.e., Notch, it is usually proposed that these fragments go to the nucleus and regulate, in concert with additional cofactors, gene transcription. This model has been validated extensively for Notch. The functional significance of the other intracellular domains has, however, been investigated to a much lesser extent, with one exception, i.e., the APP intracellular domain (AICD). The literature, with regard to the function of AICD, is full with contradiction (Table 2Go), and it is not possible yet to make any definitive statements. In the discussion on potential AICD functions, the following points should be taken into consideration. First, the large Notch intracellular domain (110 kDa) contains a nuclear localization signal, a RAM domain, six ankyrin repeats, and a COOH-terminal PEST domain and indeed binds and regulates activity of transcription factors. The AICD in contrast is only 50 amino acids long and has a very relaxed conformation. This implies the possibility that this peptide will adapt, via an induced fit model, to many binding proteins, a phenomenon called "binding promiscuity". Thus overexpression experiments with this fragment need careful controls (for discussion, see Ref. 64). Second, the various deficiencies in the APP knockout mice appear to be largely rescued by the soluble APP ectodomain, indicating that absence of the AICD causes only subtle physiological defects (65). This said, we cannot exclude that AICD or, mutatis mutandi, other "ICD" have important signaling functions in and out of the nucleus, and we refer to Table 1Go for specific references addressing this question for different ICDs. For most proteins cleaved by regulated intramembrane proteolysis, further work is indeed needed to explore the physiological roles of the cleavage products. The study of Notch signaling provides a good standard. Kopan and colleagues mutated, by an elegant knock-in strategy, Valine1744 in the endogenous mouse Notch1 gene and found severe Notch signaling deficiencies in these mice (32), implying that release of the NICD is essential for this process. It should be noticed that the Valine1744 mutation actually does not inhibit Notch cleavage but shifts, because of the relaxed specificity of {gamma}-secretase (51, 80), the cleavage site so that a novel NICD with amino-terminal leucine is generated (82). The N-end rule for protein stability predicts that an NH2-terminal valine will stabilize, whereas an NH2-terminal leucine will destabilize the NICD protein (20), explaining the Notch-deficient phenotype of the mice. Actually, differential cleavages of Notch might be a way to regulate the strength of Notch signaling (82).


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  		Table 2. Proposed functions of AICD as derived from the literature
 
In conclusion, the cleavage of integral membrane proteins by the presenilin/{gamma}-secretase complex likely contributes to a variety of biological functions. However, this hypothesis needs to be balanced with the possibility that {gamma}-secretase is responsible for the clearance of transmembrane fragments generated by protein shedding (39). Indeed, the fact that intracellular domains become released during this degradation process does not necessarily imply that they have also a signaling function. Moreover, most of these fragments are degraded very rapidly in the cytoplasm.


   Heterogeneity of the {gamma}-Secretase Complexes Provides a Novel Twist to the Debate
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 
Different genes encode presenilin 1, presenilin 2, Aph-1a, and Aph-1b in the human genome, and subtle alternative spliced variants of all these genes have been described (1, 19, 66). Furthermore, in rodents, the Aph-1b gene has been duplicated in a tandem repeat as Aph-1c, adding additional complexity when studying mouse models (73). With antibodies against the individual {gamma}-secretase complex components, it has been shown that presenilin 1 and presenilin 2 or Aph-1a and Aph-1b are never in the same complex (28, 76). Thus several different {gamma}-secretase complexes coexist next to each other, even in the same cell line. If a 1:1:1:1 stoichiometry is considered (67), then every variant subunit (including the alternatively spliced forms) generates a different complex. Although alternative splicing of a few amino acids might have little effect on the biochemical properties of the complex, it could still affect the subcellular localization and, therefore, the substrates that are seen. The different genes, on the other hand, will generate considerably different {gamma}-secretases since the primary amino acid sequence of presenilin 1 and 2 differs ~33% and that of Aph-1a and Aph-1b even differs ~43%. Some preliminary evidence suggests indeed that such different {gamma}-secretases have different biochemical properties. Presenilin 2, for instance, appears on a per mol basis a much less efficient protease than presenilin 1 for APP cleavage and generation of Aβ peptide (3, 41, 56). Overexpression experiments alone are, however, not sufficiently sensitive to dissect the fine kinetic properties of these enzymes (77), and novel assays need to be developed. Genetic knockout experiments in mice, on the other hand, have already shown that the different enzymes have quite different physiological properties. For instance, Aph-1a complexes are essential for Notch signaling (52, 73), whereas the Aph-1b-complexes seem to be more specific for the central nervous system and contribute little or nothing to Notch signaling (73). The knockout phenotypes of presenilin 1 and 2 are also very different, with presenilin 1 again mainly involved in Notch signaling and presenilin 2 having more subtle functions in lung and liver (reviewed in Ref. 54). It should indeed be taken into account that in vitro experiments can only show whether a protease can cleave a given peptide and that only in vivo experiments can show whether a given protease and a specific substrate meet in real life.


   Non-{gamma}-Secretase Functions of Presenilins
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
{gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 
Several studies have implied presenilin in nonprotease, {gamma}-secretase-independent functions. It is not obvious to provide hard evidence, because such claims as genetic presenilin knockout (to assess presenilin function) and pharmacological knockout of {gamma}-secretase (to assess the "protease"-dependent functions of presenilin) are difficult to compare in vivo. In fact, the best way probably to prove that a certain function of presenilin is independent of its proteolytic function is by demonstrating its loss in a presenilin genetic knockout model and its rescue with a catalytic inactive (aspartyl) mutant of presenilin in the same model. We summarize briefly here some functions that possibly are independent from proteolytic activity.

β-Catenin signaling
Presenilin interacts with β-catenin and other members of the armadillo family (101, 102). One series of evidences suggest that presenilin 1 acts as a scaffold to present β-catenin for phosphorylation by PKA and GSK-3β, followed by rapid proteasomal degradation (35). This pathway seems to run in parallel to the well known Wnt-regulated Axin-mediated pathway that also controls phosphorylation and turnover of β-catenin (9). As we will discuss below, this pathway has been implicated in the skin cancer associated with presenilin knockout mice, but it remains unclear whether this phenotype is indeed only a consequence of reduced β-catenin turnover. An alternative model to explain the β-catenin-presenilin interactions has elegantly been worked out by Robakis and coworkers. In their model, presenilin forms complexes with cadherins at the cell surface, and the interaction with β-catenin mainly occurs via E-cadherin. This interaction is {gamma}-secretase activity dependent, since proteolysis of E-cadherin disassembles the complex and redistributes β-catenin in the cell (53, 72).

Ca2+ signaling
Quite some evidence suggests a role for presenilin in Ca2+ homeostasis. Both {gamma}-secretase-dependent [possibly via AICD (44)] and -independent mechanisms have been proposed. Loss of function of presenilin, either by genetic knockout or by introducing mutations causing familial AD, results in Ca2+ overloading in the endoplasmic reticulum (43, 45, 59, 84). Inositol 1,4,5-triphosphate (InsP3)-mediated intracellular Ca2+ release (45, 46), ryanodine-sensitive Ca2+ pools (6), and capacitative calcium entry (CCE) (43, 98) were shown to be disturbed by presenilin clinical mutations (for review, see Ref. 40). The molecular details of how presenilin influences Ca2+ homeostasis remain unclear, but a recent finding might provide a breakthrough. Indeed, presenilin itself seems to form Ca2+ leak channels that facilitate passive Ca2+ leak across the endoplasmic reticulum membrane (59, 84). This function of presenilin is clearly independent of its {gamma}-secretase activity since it is maintained in Aph-1-deficient cells, which only contain full-length, proteolytical-inactive presenilin and can be rescued with the aspartyl-mutated presenilin in presenilin-deficient cells (84). Since the channel properties of presenilin could be demonstrated also in reconstituted planar membranes, this finding provides the clearest proof of a presenilin function that is independent of the {gamma}-secretase complex.

In vivo models of presenilin function
The physiological functions of presenilin have been extensively investigated in various knockout mouse models (reviewed in Ref. 54). In most cases, deficits in Notch signaling can explain the observed phenotypes (cancer, immune disorders, developmental defects). However, somite formation is completely abrogated in presenilin 1- and 2-deficient mice, whereas the first somites are still formed in nicastrin- or Notch-deficient mice (31), suggesting the possibility of a non-{gamma}-secretase function for presenilin.

Interestingly, in the context of AD, mice lacking presenilin in the forebrain exhibit age-related impairments in LTP and in hippocampal memory, followed by synaptic and neuronal degeneration. Synaptic levels of the NMDA receptor and CaMKII are decreased, and decreased levels of CBP and CREB/CBP target genes, such as c-fos and BDNF, are observed (68). The authors suggested that part of the phenotype could be explained by non-{gamma}-secretase functions of presenilin in molecular trafficking, as has also been suggested by other authors (58, 87). How presenilin affects protein trafficking, however, remains unclear.

Finally, Khandelwal et al. used Physcomitrella patens, a kind of moss that expresses presenilin and {gamma}-secretase proteins but not Notch receptors or APP (36). When the presenilin homolog was inactivated in this species, abnormalities in the cytoskeleton, which could be rescued with human presenilin containing aspartyl mutations, were observed.


   {gamma}-secretase in AD and Cancer
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
Conclusions and Perspectives
 References
 
The importance of presenilins in AD is obvious since more than 160 mutations in PSEN1 and 10 mutations in PSEN2 genes have been identified, all causing autosomal-dominant inherited AD (http://www.molgen.ua.ac.be/ADMutations/). The only other gene known to contain mutations causing AD is APP. Thus mutations in the protease and in the substrate can cause the disease, which forms one of the corner stones of the "amyloid cascade hypothesis" (26). As explained above, presenilin/{gamma}-secretase can cleave its substrates at different positions, which results in a spectrum of Aβ peptides that vary at the carboxy terminus. The disease causing mutations in presenilin has variable effects on the spectrum of Aβ peptides released from transfected cells (3), but consistently more long (≥Aβ42) and less short (≤Aβ40) peptides are generated. Such changes in the spectrum of Aβ peptides are underlying the increase in the relative amount of Aβ42/Aβ40' which is one of the most reproduced findings in material of patients with presenilin mutations (69). Since the carboxyterminal residues determine the aggregation properties of the peptide (33), it is likely that the relative ratio of peptides determines to a large extent the amount and quality of the Aβ oligomers, which are seen more and more as the toxic mediators in the disease process (25). Obviously, given the central role of {gamma}-secretase in this process, huge efforts are going on to develop inhibitors and modulators of this activity for the treatment of AD (12).

The major hurdle for such therapies is the involvement of {gamma}-secretase in Notch signaling, as discussed above. The recent insight that different {gamma}-secretase complexes exist and are involved to different extents in Notch and APP processing suggests at least theoretically that developing inhibitors for specific {gamma}-secretase complexes could become a useful strategy.

The predominant role of presenilin/{gamma}-secretase in Notch signaling has indeed led to serious problems with the available broad spectrum {gamma}-secretase inhibitors. For instance, blocking Notch in the crypts of the intestinal epithelium induces differentiation to goblet cells and interferes with the normal replacement of the epithelium, explaining the gastrointestinal toxicity of {gamma}-secretase inhibitors (71, 86). But a disadvantage can become rapidly an advantage in biology, since blocking abnormal Notch activation in cancers is considered more and more a viable therapeutic strategy. For instance, about half of T-cell acute lymphoblastic leukemias display activating mutations in the Notch gene (91). Notch signaling also seems to contribute to lung cancer (38), and {gamma}-secretase inhibitors are able to turn precancerous adenoma cells in mice carrying a mutation of the APC tumor-suppressor gene into non-proliferative goblet cells (86). Thus the many {gamma}-secretase inhibitors synthesized over the last few years for AD may well turn out to have a second life in cancer research.

Presenilin has been implicated also in the control of malignant phenotypes via non-Notch signaling pathways. Presenilin (and other {gamma}-secretase components) knockout mice develop skin carcinomas (49, 96). Reduced β-catenin phosphorylation and turnover (see above) might be involved (35), but the interpretation of this phenotype is complicated, since deficient Notch signaling in skin (as opposed to what we discussed in the previous paragraph for other tissues) can cause skin cancer as well (60), and specific ablation of Notch1 in the epidermis induces β-catenin stabilization, independent of presenilin dysfunction.


   Conclusions and Perspectives
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
References
 
The role of presenilin as the catalytic site of {gamma}-secretase is established, and its crucial role in the generation of Aβ peptide makes it a prime drug target for the treatment of AD. The many physiological roles in which {gamma}-secretase has been implicated suggest that it will be difficult to circumvent side effects potentially associated with such a therapy. However, it becomes more and more clear that different complexes exist and that they might have different functions. Further work should clarify the physiological relevance of this heterogeneity. Most promising areas for further work are cell biological questions related to how these different complexes are assembled and targeted in the cell, where and how they meet their substrates, and finally how their activity is regulated.


   Acknowledgments
 
The investigators are supported by the Fund for Scientific Research Flanders; KULeuven; Federal Office for Scientific Affairs (IUAP P6/43/), Belgium, a Methusalem grant of the Flemish Government, and the EU (MEMOSAD F2-2007-200611). T. Wakabayashi was a Marie Curie fellow.


   References
Top
 Introduction
 Presenilins are Part of...
 The Presenilins in Regulated...
 Heterogeneity of the {gamma}...
 Non-{gamma}-Secretase Functions...
 {gamma}-secretase in AD and...
 Conclusions and Perspectives
 References
 

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