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Human Molecular Genetics Pages 1639-1646  

The presenilins and Alzheimer's disease
Introduction
Molecular Biology Of The Presenilins
Genetics Of The Presenilins
Cell Biology Of The Presenilins
The Presenilins, SEL-12 And Notch
Effect Of Presenilin Mutations On A[beta]42(43)
Conclusion
Acknowledgements
References

The presenilins and Alzheimer's disease

The presenilins and Alzheimer's disease

Michael Hutton*, John Hardy

Neurogenetics Laboratory, The Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Received May 27, 1997

The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi. The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-[beta]42(43) being produced from the metabolism of the amyloid protein precursor. Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis. Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.

INTRODUCTION

Alzheimer's disease (AD) is a neurodegenerative condition that is associated with progressive memory loss that leads to dementia and eventually death. At autopsy two characteristic lesions, `plaques and tangles', are seen in the brains of affected patients. Tangles are made up primarily of paired helical filaments composed of the microtubule-associated protein tau. Plaques can be subdivided into `classical' and `diffuse' types. In both cases amyloid in the form of fibrils of the A[beta] peptide is the primary deposit. In the `classical' plaque, a dense central core of amyloid is surrounded by diseased neurons that project neurites, towards and around the core. In the diffuse plaque the amyloid deposit is more amorphous and is not associated with significant cell loss. It is presently unclear what the relationship is between the plaque and tangle or to what degree the amount of plaque and tangle pathology is associated with disease state. This has led to the suggestion that the pathology is a marker for the disease rather than being causative (for review see ref. 1).

To date four loci have been associated with Alzheimer's disease; the first on chromosome 21 was the amyloid precursor protein (APP) (2). Mutations in APP were identified in a series of large families with autosomal dominant early-onset AD, onset age 45-65 years (2). APP is processed by cellular proteases known as [alpha], [beta] and [gamma] secretases. The [alpha]-secretase cleaves within the A[beta] peptide sequence in APP preventing the generation of A[beta]. In contrast the [beta]-secretase cleaves at the N-terminus and leads to the generation of the A[beta] peptide, after cleavage by a [gamma]-secretase. The site of cleavage by the [gamma]-secretase enzyme(s) is C-terminal of residue 712. If cleavage occurs at residue 712-713, short A[beta] (A[beta]40) results; if it is after residue 714, long A[beta] [A[beta]42(43)] is generated. The A[beta] peptide is the primary component of amyloid deposited in the brains of AD patients. All of the mutations found in APP occur either within or flanking the A[beta] peptide sequence and all (that result in an AD phenotype) affect the processing of APP to A[beta] such that either more total A[beta] is generated or more of the amyloidogenic A[beta]42(43) species alone (Table 1). This longer form of A[beta] is deposited selectively in the early stages of amyloid deposition. These observations led to the hypothesis that the deposition of amyloid, made up principally of A[beta]1-42(43), was the central event in the initial pathogenesis of AD: `the amyloid cascade hypothesis' (Fig. 2). However, mutations in APP are rare and to date have only been identified in [sim]20 families with autosomal dominant AD (for review see ref. 3).

The second locus on chromosome 19 was identified as apolipoprotein E (ApoE). ApoE exists in three variants, ApoE2, ApoE3 and ApoE4. The inheritance of one or two copies of the ApoE4 allele increases the risk of developing AD that is not inherited in an autosomal dominant fashion (4). In addition the age of onset of disease decreases with increasing ApoE4 gene dose (4). However, inheritance of ApoE4 is a risk factor for AD and is not sufficient for development of disease. In addition the observation that ApoE4 is also associated with several other neurodegenerative conditions has led to the suggestion that its role in AD is not specific and reflects a more general function in the neuronal response to injury (for review see ref. 5).

More recently the positional cloning of the presenilin 1 (PS-1) gene on chromosome 14 identified the major locus for autosomal dominant AD (6). The age of onset in families with PS-1 mutations is the earliest observed (28-60 years) (7). Database comparisons with the PS-1 sequence identified two expressed sequence tags with significant identity suggesting the presence of a second related gene, presenilin 2 (PS-2) (8-10). The subsequent identification of a mutation in PS-2 in a series of German families originally from the Volga valley in Russia confirmed the significance of this gene in AD pathogenesis (8,10). Mutations identified in the PS-2 gene to date appear to result in AD with a later and more variable age of onset than mutations in PS-1 (8,10).

This review will focus on recent progress in examining the normal cellular function of the presenilins and how this relates to their dysfunction in AD.

MOLECULAR BIOLOGY OF THE PRESENILINS

The structures of the PS-1 and PS-2 genes are remarkably similar. Each gene consists of a total of 13 exons with 10 exons comprising the coding sequence (exons 3-12); the 5[prime]UTR is contained on four separate exons (1a, 1b, 2 and 3) (9,11-13). [In this article, for the sake of simplicity, we have kept to our original numbering system for the presenilin exons which predated the discovery of the most 5[prime] exon (9,11).] In the PS-1 gene exons 1a and 1b are mutually exclusive and represent alternate transcriptional start sites. The PS-1 promoter contains consensus TATA box and CAAT box sequences; in addition, multiple STAT elements are observed that are involved in transcriptional activation in response to signal transduction (13). The PS-2 promoter in contrast lacks consensus TATA and CAAT boxes but contains regions of GC rich sequence upstream of two transcriptional start sites (Hutton and Hardy, manuscript in preparation). The equivalent positions of intron/exon boundaries in the coding sequence of both genes are also virtually identical, consistent with the idea that they are derived from a common ancestral gene that underwent gene duplication (11,12).

Both presenilin genes undergo alternate splicing; however, the pattern is different in PS-1 and PS-2. In PS-1 alternate use of the splice donor site for exon 3 results in the inclusion/exclusion of codons 26-29 (VRSQ) (9). The inclusion of the VRSQ motif creates potential phosphorylation sites for protein kinase C and casein kinase II. However, the relative levels of the two transcripts do not appear to vary markedly in all tissues examined, suggesting that there is little tissue-specific regulation of this alternate splice event (9,14). In PS-2 the VRSQ motif is only partially conserved (WRSQ) and as a result is not alternately spliced (11). A second splice variant in PS-1 results in the presence or absence of exon 8 although this has only been observed in leukocytes (10,11). The importance of this variant is unclear. However, it may be significant that exon 8 contains the highest density of AD mutations (7) and the equivalent exon is also alternately spliced in PS-2 (10,11,15). A further variant in PS-2 results in the alternate splicing of exons 3 and 4 (11); the absence of these exons results in the loss of the normal translational start site. Transcripts lacking exons 3 and 4 make truncated proteins in transfected cells, presumably using an alternative downstream ATG codon (Haass, Hutton and Hardy, unpublished data).

Two major transcripts are observed for both PS-1 and PS-2 on northern blots. PS-1 mRNAs are [sim]2.7 and 7.5 kb with the longer transcript thought to be generated by alternate polyadenylation site usage. PS-2 mRNAs are 2.3 and 2.6 kb in size. The PS-1 and PS-2 mRNAs encode proteins that display 67% identity to each other (6,8,10). The structure of the presenilin proteins (Fig. 1) is proposed to contain eight transmembrane (TM) domains, which display greatest conservation between ps-1 and ps-2. TM6 and TM7 are linked by a long acidic loop of relatively low conservation and variable length. The topology of the presenilins was determined using selective permeabilization with the pore-forming toxin SLO which does not disrupt the ER/golgi membranes, followed by epitope-specific antibody tagging which demonstrated that the N- and C-termini of the protein are orientated towards the cytoplasm (16). This result is consistent with the absence of an obvious signal peptide at the N-terminus of the presenilins. The TM structure of the presenilins (Fig. 1) is based largely on work performed on the Caenorhabditis elegans protein sel-12 (see below), that displays a high degree of homology with ps-1 and ps-2. This study used a [beta]-galactosidase-hybrid protein approach which is based on the observation that [beta]-galactosidase is active within the cytoplasm of cells but not the extracytosolic compartment. Constructs containing the SEL-12 cDNA truncated after each of 10 predicted TM domains, based on hydrophobicity analysis of sel-12, fused to LacZ were used to generate transgenic worms. The worms were then stained for [beta]-galactosidase activity (17). Only in constructs where the [beta]-galactosidase was orientated into the cytosolic compartment was staining observed. This demonstrated which putative TM domains actually spanned the membrane; to confirm the results, a synthetic TM domain was also added to each construct which reversed the results of the original construct. As a result, eight of the 10 putative TM domains were found to span the membrane (Fig. 1).


Figure 1 Transmembrane structure of PS-1. The sites of mutations in the PS-1 protein are indicated, for a list of mutations see ref. 24. PS-2 has a similar structure with mutations at N141I (N135 in PS-1) and M239V (M233 in PS-1). The cluster of mutations in the TM2 domain are thought to lie on one side of the presumed [alpha]-helix. Residues encoded by exon 9 are indicated as these are lost in the [Delta]9 mutation that blocks processing of PS-1. The location of the PS-1 endoproteolytic cleavage site (residues 291-299) is marked.


Figure 2 Presenilins in the amyloid cascade hypothesis. The initial steps in the amyloid cascade hypothesis are shown with the effect of the presenilin and APP mutations on APP processing indicated. The C-100 fragment is the C-terminal fragment starting at Met621 that is generated by [beta]-secretase cleavage of APP. P3 is the shorter non-amyloidogenic peptide derived by [alpha]-secretase cleavage followed by [gamma]-secretase cleavage. The precise inter-relationship between A[beta]42(43), amyloid deposits and the development of disease is presently unclear as indicated by question marks in this section of the diagram.

Both ps-1 and ps-2 are proteolytically cleaved by an as yet unidentified protease(s) to generate two polypeptides (18-20). In ps-1 the N-terminal fragment is 27-28 kDa and the C-terminal fragment 17-18 kDa, the full-length protein is observed as a [sim]43 kDa species. The full-length ps-2 protein (53-55 kDa) is cleaved to a 35 kDa N-terminal fragment and a 20 kDa C-terminal fragment (21). For both presenilins the predominant species that are observed in cultured mammalian cells and in the brain are the processed fragments. The major site of the proteolytic cleavage in ps-1 (Fig. 1) has been localized to residue 292 in exon 9 although cleavage at other adjacent minor positions (291-299) is also observed that generate a heterogeneous population of N- and C-terminal fragments (22). The presenilins are also thought to be degraded via a proteasome-mediated pathway after ubiquitination of the full-length protein, although the relationship of the two processing and degradation pathways has, as yet, not been determined (23).

Table 1 Known routes to Alzheimer's disease
MutationEffect on APPEffect on A[beta]
Down's syndromeMore APP productionMore A[beta]42(43) and A[beta]40
APP670/1 (Swedish)Potentiation of [beta]-secretaseMore A[beta]42(43) and A[beta]40
APP716 (Florida)Alteration of site of [gamma]-secretase cutMore A[beta]42(43)
APP717 (London)Alteration of site of [gamma]-secretase cutMore A[beta]42(43)
PS-1 mutationsSubtle alteration of APP processingMore A[beta]42(43)
PS-2 mutationsSubtle alteration of APP processingMore A[beta]42(43)
APP, amyloid precursor protein; PS, presenilin.The APP716 (Florida) mutation was recently identified in the authors' laboratory (manuscript in preparation).

GENETICS OF THE PRESENILINS

More than 40 mutations have been described in PS-1 that cause early-onset AD, while only two have been described in PS-2. Mutations in PS-1 cause disease with an early (28-60 years) and consistent age of onset while the age of onset in PS-2 families is later and more variable (35-82 years) (7,24). Only one PS-1 mutation (I143F) in an English family has been described with possible incomplete penetrance (25). At present there is no evidence that ApoE genotype affects the age of onset in PS-1 families (26) although there does appear to be a weak association between the rate of disease progression and ApoE4 in the PS-2 Volga German families (27). All mutations in both PS-1 and PS-2 are missense mutations that affect residues conserved between both presenilins. The one exception is a mutation in PS-1 that destroys the splice acceptor site for exon 9 (usually referred to as the [Delta]9 mutation); this in turn results in the inframe deletion of exon 9 from the mutant transcripts and in an amino acid substitution (S290C) (28). The loss of exon 9 from the PS-1 mRNA also has the effect of removing the protease cleavage site from the protein with the result that ps-1 [Delta]9 is not processed in any of the mammalian cell lines in which it has been transfected (19). This mutation has been observed in families from England, Japan and Australia (28-30). The Australian kindred has an interesting phenotype in which the presenting symptom is usually paraplegia. Whether this is a direct consequence of the nature of the PS-1 [Delta]9 mutation has yet to be determined (29). None of the other PS-1 or PS-2 mutations block presenilin processing in all cell types (18), in this manner, although it has been suggested that the mutations lead to increased levels of the N- and C-terminal fragments by partially blocking proteasome degradation of the presenilin protein (23). No nonsense or frameshift mutations in the presenilins have been observed and the [Delta]9 mutation preserves the open reading frame. Therefore, it seems unlikely that the mutations cause disease through a simple loss of function, since mutations that would be expected to completely block presenilin function have not been found. A more likely explanation would appear to be that the mutations cause a gain of dysfunction or that the mutant protein blocks the function of the wild-type protein through a dominant-negative mechanism.

Mutations have been identified that alter conserved residues throughout ps-1 (Fig. 1). However, there are at least two distinct clusters of mutations. One of these is at the N-terminal end of TM2 (9,31), while the other cluster extends from TM6 into the N-terminal region of the long acidic loop between TM6 and TM7 (exon 8) (7,15). The proximity of the second cluster to the site of cleavage in the presenilin protein may be significant to the effect of these mutations on the function of ps-1. The mutations in TM2 in ps-1 are all predicted to lie on one face of the proposed transmembrane [alpha]-helix; this pattern also extends to the residue (PS-1 N135/PS-2 N141) that is mutated in both presenilins (10,31). It seems likely that the alignment of these mutations underlies their pathogenicity. Mutations in the two clusters give significantly different ages of onset when compared with each other; the TM2 cluster has a lower mean age of onset than the cluster around TM6 (mutations in the rest of the protein have an even higher mean age of onset). However, while multiple factors, not just related to the presenilin mutation, will affect the age of disease onset in a family, it appears likely that it is the nature of the amino acid substitution at a given site that has the more significant effect rather than the position of the mutation in the protein. A clear example of this is at position PS1-I143 at which the substitution I143T in a Belgian family gives an onset age of [sim]30 while the substitution I143F in an English family leads to an onset age of [sim]55 and is also present in one elderly unaffected individual (14,25).

The prevalence of presenilin mutations in AD has been difficult to estimate due to the effect of ascertainment bias in the collection of early-onset AD samples which has clearly favored large families with apparent autosomal dominant inheritance (32). Initial suggestions that PS-1 mutations accounted for up to 70% of early onset (below 65) AD cases were considerable overestimates. In a study of a Dutch population-based early-onset AD series the frequency of PS-1 mutations was 18% in families with autosomal dominant inheritance, 9% in familial AD with no clear inheritance pattern and 6% in early-onset AD as a whole (33). In terms of the number of cases of early onset disease (<65 years) the effect of ApoE is likely to be more important than mutations in the presenilins and APP (34). In our series, all families with clear autosomal dominant inheritance have now been explained by mutations in either PS-1 (14 mutations, 14 families) or APP (three mutations, five families). The remaining early-onset families are too small to determine a clear mode of inheritance; however, significantly these remaining families have excess levels of the ApoE4 allele (32,35). Even with allowances for ascertainment bias, it appears certain that PS-1 mutations are more common than mutations in either APP or PS-2; which together probably account for <20% of the remaining autosomal dominant cases.

An intronic polymorphism in PS-1 between exon 8 and exon 9 has been reported to show a significant association with late onset disease (36). The association was with the homozygote genotype for the more common allele and was observed in two series of late-onset patients from the USA. The odds ratio for the association was calculated to be [sim]2 and the attributable fraction was [sim]0.2 (36). However, subsequent studies in different datasets have given different results with several reports confirming the association (37-39) but several others describing no association (41-44). None of the subsequent reports of positive association with the intronic polymorphism have observed as large an effect as described in the original study. Taken together these data suggest that it is unlikely that the polymorphism itself influences the risk of developing late-onset AD, although its proximity to the exon 8 splice donor site led to the suggestion that it may have an effect on splicing (35). If the reported association of this polymorphism with AD is correct, it is most likely that it is in linkage disequilibrium with biologically relevant variability elsewhere in the PS-1 gene.

CELL BIOLOGY OF THE PRESENILINS

In the brain, both in situ hybridization and immunohistochemistry studies indicate that PS-1 and PS-2 are predominantly expressed in neurons (45,47); however, expression in glia has also been observed (46). Northern blot results indicate that PS-1 and PS-2 mRNA is present in a wide variety of peripheral tissues. Expression of PS-1 appears to be at approximately equivalent levels in all tissues (6,8,10,45) while significant variability is observed in the level of PS-2 expression (10,12,13), with highest levels observed in heart, pancreas and brain. In contrast, western blot analysis has revealed significant variation in ps-1 protein levels in different tissues (46), with highest levels in testis and lung, suggesting that there are potentially differences in PS-1 translation efficiency, mRNA stability or protein half-life between different tissues. Intracellular localization of the ps-1 and ps-2 proteins reveals that they are present predominantly in the endoplasmic reticulum with some immunoreactivity observed in the early Golgi (45,47-49). No significant difference is observed between the distribution of the wild-type and mutant presenilin proteins (45). In neurons, ps-1 and ps-2 are principally observed in the cell body and in the dendrites (47).

Analysis of the phosphorylation of the presenilins in transfected cells, in one study (48), indicated that while the full-length ps-2 is phosphorylated, little or no phosphorylation of full length ps-1 occurs. ps-2 is phosphorylated at three serine residues in an acidic stretch of amino acid residues at the N-terminus of the protein that is absent in ps-1, the three serines form part of two casein kinase 2 sites and a casein kinase 1 site (48). Deletion of the acidic stretch containing the three serines almost completely inhibits the observed phosphorylation of ps-2. No evidence of direct phosphorylation of the full-length presenilins by protein kinase C was observed. However, a second report (49) presents conflicting data that indicate that both full-length ps-1 and ps-2 are phosphorylated predominantly on serine residues. In this latter study the phosphorylation of ps-1 was strongly increased by treatment of the transfected cells with the phosphatase inhibitor okadaic acid (49); however, again no evidence of phosphorylation by protein kinase-C was observed. In contrast the [sim]17-18 kDa C-terminal fragment of ps-1 generated by proteolytic cleavage is phosphorylated by protein kinase C (50). This phosphorylation occurs at serine residues in the TM6-TM7 loop domain of ps-1 and can be induced either by direct stimulation of PK-C with phorbol-12,13-dibutyrate or by activation of the acetylcholine receptor signaling pathway with the muscarinic agonist carbachol (50). The ps-1 protein with the exon 9 deletion, which does not undergo cleavage, is not phosphorylated in a similar manner, suggesting that it is the C-terminal fragment that is phosphorylated by PK-C as opposed to the full-length protein which then undergoes rapid proteolysis (50). Since the activation of PK-C stimulates the [alpha]-secretory processing of APP (51), thus increasing the amount of secreted APPs-[alpha], the phosphorylation of the ps-1 C-terminal fragment parallels the secretion of APPs.

The cleavage of both ps-1 and ps-2 full-length proteins into N- and C-terminal fragments by an as yet unidentified protease is a tightly regulated event (19,52). Overexpression of either PS-1 or PS-2 in transfected cell lines or in transgenic mice (52) leads to a marked increase in the amount of detectable full-length protein although only a relatively small increase is observed in the level of the fragments. The [Delta]9 deletion mutant removes the cleavage site and as a result the cleavage fragments are not observed; instead, just a smaller (39 kDa) holoprotein band is seen (19). This effect is observed in all cell types into which PS-1 cDNAs bearing this mutation are transfected (19,48,52). However, this is the only mutation in which such a clear effect on cleavage is observed. One report (18) described similar effects with the M146V and A246E mutations in PC-12 cells although in other cell types these mutations do not block cleavage (19,48,52). It has also been reported that missense mutations in PS-2 increase the level of the N- and C-terminal fragments; this was observed in stably transfected inducible human H4 neuroglioma cell lines (21). The mechanism by which the mutations increase the level of the fragments is presently unclear although the observation that presenilins are also degraded by a non-specific pathway that is probably mediated by the proteasome (21,23) has led to the suggestion that the missense mutations may partially block proteasome mediated degradation of the presenilins thus leading to an increase in cleavage to the N- and C-terminal fragments (21). The relevance, if any, of these effects on presenilin processing, by both the [Delta]9 mutation and the other missense mutations, to AD pathogenesis is presently unclear.

A further proposed role in cellular function for the presenilins is in the control of apoptosis (53-55). This was originally suggested based on the observation that a partial antisense cDNA for PS-2 (ALG-3) was able to block apoptosis in T hybridoma cells (54). Subsequent studies have also found that transfection of the wild-type PS-2 cDNA induces apoptosis in PC12 cells on serum withdrawal and that the PS-2 N141I mutant cDNA will induce increased apoptosis in PC12 cells even without serum withdrawal (55). This suggests a mechanism by which the mutations might induce cell death or at least cellular stress in AD. Whether this relates to the pathogenicity of the presenilin mutations remains unclear.

THE PRESENILINS, SEL-12 AND NOTCH

The functions of the presenilins have yet to be determined. However, the most informative observation to date has been the identification of two proteins in C.elegans, sel-12 and spe-4, with significant homology to the presenilins ([sim]50 and [sim]25% identity, respectively). The vast majority of mutations (>80%) in PS-1 and PS-2 that are associated with early-onset AD occur at residues which are conserved in SEL-12 which displays the greatest identity with the presenilins (56). spe-4 is involved in the formation and stabilization of the fibrous body membrane organelle during spermatogenesis; loss of function mutations in this gene affect the transport of proteins to spermatids (57), thus suggesting a role for spe-4 and by extension the presenilins in protein trafficking.

SEL-12 was identified as part of a screen for genes capable of reverting a multivulva phenotype caused by constitutive expression of LIN-12 (56). lin-12 is a member of the notch family of receptors that are involved in intercellular signaling and the determination of cell fate through lateral inhibition (56). Further support for a role of the presenilins in notch signaling comes from the observation that PS-1 knockout mice show developmental abnormalities similar to those seen in mice in which other components of the notch system have been knocked out (58-60). However, the precise relationship between lin-12 and sel-12 in the signaling cascade in cellular differentiation has yet to be determined. Genetic analysis revealed that loss of function mutations in SEL-12 result in an egg-laying defective (egl) phenotype that is inherited in a recessive manner (56). The egl phenotype is characterized by the accumulation of eggs in the body of the parent nematode. Recent studies have demonstrated that the egl phenotype can be rescued not only by creating transgenic C.elegans lines expressing wild-type SEL-12, but also PS-1 and PS-2, although the activity of the PS-1 and PS-2 cDNAs in the rescue assay appears to be slightly lower than for SEL-12 (61,62). In these experiments SEL-12, PS-1 or PS-2 cDNAs were expressed in constructs containing either the LIN-12 or SEL-12 regulatory regions and rescue was assessed by assaying hermaphrodites for their egg-laying ability. Thus, it would appear that the human proteins are functionally equivalent in C.elegans to sel-12 (61,62). In addition, transgenic worms generated with PS-1 cDNAs bearing missense mutations displayed markedly reduced ability to rescue the egl phenotype (61,62). It would therefore seem likely that these mutants, which each cause AD, have at least a loss of function (hypomorphic) component. In contrast, the PS-1 [Delta]9 cDNA was found to rescue the phenotype to a level similar to wild-type PS-1 (61,62), although one study did report reduced rescue activity for the [Delta]9 construct if transgenic nematode lines were generated with less DNA and, therefore, with lower numbers of copies of the rescue construct (61). This suggests that the action of this unique deletion mutant may differ from that of the missense mutations. This discrepancy would also be consistent with the complete inhibition of presenilin endoproteolytic cleavage in all cell lines that is observed only with the [Delta]9 mutation (19,48,52).

EFFECT OF PRESENILIN MUTATIONS ON A[beta]42(43)

Mutations in both PS-1 and PS-2 are associated with increased production of A[beta]42(43), the amyloidogenic form of A[beta] that is deposited selectively and early in AD (63). This observation was initially made in the plasma and in the media from cultured fibroblasts in patients from families with autosomal dominant AD compared with control subjects (64). A similar increase is not found in the level of A[beta]40. Measurements of A[beta]42(43) and A[beta]40 were made in families with three different PS-1 mutations and in a Volga German family with the PS-2 mutation, using a sandwich ELISA assay that specifically detects the different forms of A[beta]. This increase in A[beta]42(43) was similar to that described in the same study in the plasma from families with APP717 mutations which also do not significantly effect the level of A[beta]40. The APP K/M670/1N/L mutation increases the levels of both A[beta]42(43) and A[beta]40. Thus, all the mutations, both in APP and the presenilins, increase A[beta]42(43) suggesting a common pathological pathway by which these mutations cause AD (64). In contrast, the majority (90%) of plasma samples from late-onset `sporadic' AD cases did not show an increase in A[beta]42(43) which suggests that the increase in the presenilin and APP families is a consequence of the mutations and not an indirect consequence of the disease state (64). A small proportion ([sim]10%) of late-onset AD cases (64) do show increased A[beta]1-42 in their plasma, however, suggesting that high A[beta]1-42 may also be a cause of disease in a significant subset of late-onset patients.

Subsequent studies have demonstrated increased production of A[beta]42(43) in transfected cell lines and also in the brains of transgenic mice expressing mutant PS-1 and PS-2 cDNAs, consistent with the original observation in patient fibroblasts and plasma (52,65-67). However, there is no clear link between the level of A[beta]42(43) observed with each mutation and the severity of the associated phenotype (66; Hutton and Hardy, unpublished data) as represented by the age of disease onset in families in which the mutations were identified. Many factors are probably responsible for this including variations in clinical ascertainment and also the effect of different genetic backgrounds on age of onset. Interestingly the [Delta]9 mutation has consistently been found to give the highest A[beta]42(43) levels (52; Hutton and Hardy, unpublished data) when compared with PS-1 missense mutations, in transfected cell analysis. This is despite the fact that the ages of onset in families bearing this mutation are not particularly early and is another demonstration of the unusual nature of this mutation.

The mechanism by which the presenilin mutations alter the production of A[beta]42(43) has yet to be determined; one possibility is that a direct interaction between presenilins and APP occurs that causes a subtle alteration in the cleavage of APP by single or multiple [gamma]-secretase enzymes. Two observations are consistent with this hypothesis: first, the presenilins and APP are colocalized in the endoplasmic reticulum and early Golgi, and second, the recent demonstration that ps-2 and APP form stable complexes in transfected cells (68). In this study mammalian cells were first cotransfected with APP and PS-2. Immunoprecipitation of ps-2 revealed that a proportion of APP was associated with ps-2 immunocomplexes; similarly, precipitation of APP revealed associated ps-2 molecules. The interaction was non-covalent and was restricted to immature forms of APP, suggesting that the interaction occurred during transit of APP through the endoplasmic reticulum consistent with the subcellular localization of ps-2. The same report (68) also described a decrease in the secretion of APP in response to the co-expression of PS-2 suggesting that the presenilins are directly involved in the trafficking and processing of APP. However, the interaction between APP and PS-2 was not obviously affected by the N141I (Volga, German) mutation, although a subtle effect undetectable in the immunoprecipitation paradigm, could not be ruled out (68). Thus, the mechanism by which the mutations affect APP processing remains unclear. The presenilin mutations may directly influence [gamma]-secretase cleavage of APP while complexed with ps-1 or ps-2 or the mutations may cause a subtle alteration in the trafficking of APP such that a greater proportion enters a pathway that leads to the generation of A[beta]42(43).

CONCLUSION

Early-onset disease caused by mutations in APP and the presenilins is most likely related to an increase in the production of A[beta]42(43) since all mutations in each of these genes lead to this effect (Table 1, Fig. 2). It seems unlikely that this increase is an epiphenomenon, as A[beta]1-42(43) is the more amyloidogenic species of A[beta] that is deposited selectively and early in AD (63,69). In addition, the increased tendency of A[beta]42(43) to form fibrils (70) also means that this species is potentially the more cytotoxic form of A[beta].

It is not clear whether the effects of the presenilin mutations on A[beta]42(43) production reflect a specific effect of the presenilins on APP processing. The data derived from the analysis of the C.elegans homologues strongly suggest that the functions of the presenilins do not uniquely relate to APP, but rather that they have a more general role, possibly in the intracellular trafficking of membrane proteins. This is also consistent with the proposed involvement of the presenilins in embryonic development (58,59,70) and the link between the presenilins and apoptosis (53-55). However, the observed interaction between ps-2 and APP suggests that the involvement of presenilins in APP processing, although not specific, is direct. If this is the case, the role of the presenilin mutation in AD may merely reflect a minor alteration in presenilin function in protein processing whose only obvious consequence is an increase in A[beta]42(43) which leads to disease after [sim]40 years.

Although all patients with early-onset AD caused by mutations in APP or the presenilins display increased production of A[beta]42(43), only a small proportion (<10%) of typical AD cases show a similar increase (64). These late-onset patients comprise >95% of all AD cases. It is not clear how the etiology of these patients relates to the etiology of the autosomal dominant cases. However, sporadic/late-onset AD has virtually identical pathology to AD caused by mutations in either the presenilins or APP (1,66), with both early and selective deposition of A[beta]42(43) and the formation of both neuritic plaques and tangles. It therefore seems highly likely that in both forms of the disease similar pathways to pathogenesis are at work. One possibility is that proteins responsible for the `clearance' of soluble A[beta] or that accelerate deposition of A[beta] are factors in the generation of disease in late-onset cases. Thus, a minority of late-onset cases ([sim]10%) display increased A[beta]42(43) and presumably develop disease in a manner identical to individuals with APP or presenilin mutations, while the majority of late-onset cases ([sim]90%) do not display increased A[beta]42(43) but do undergo amyloidogenesis (despite apparently `normal' A[beta] levels) due to either poor clearance of A[beta] or to the presence of other factors that accelerate fibrillogenesis and/or deposition.

ACKNOWLEDGEMENTS

Work in the authors' laboratory is supported by an NIH program project grant to M.H. and J.H. on the presenilins (AG146133).

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*To whom correspondence should be addressed. Tel: +1 904 953 0159; Fax: +1 904 953 7370; Email: hutton.michael@mayo.edu

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Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice
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S. Grau, A. Baldi, R. Bussani, X. Tian, R. Stefanescu, M. Przybylski, P. Richards, S. A. Jones, V. Shridhar, T. Clausen, et al.
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V. Beglopoulos, X. Sun, C. A Saura, C. A. Lemere, R. D. Kim, and J. Shen
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 Arch NeurolHome page
G. A. Rippon, R. Crook, M. Baker, E. Halvorsen, S. Chin, M. Hutton, H. Houlden, J. Hardy, and T. Lynch
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C. Alves da Costa, E. Paitel, M. P. Mattson, R. Amson, A. Telerman, K. Ancolio, and F. Checler
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E. S. Athan, J. Williamson, A. Ciappa, V. Santana, S. N. Romas, J. H. Lee, H. Rondon, R. A. Lantigua, M. Medrano, M. Torres, et al.
A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families
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H. Steiner, K. Duff, A. Capell, H. Romig, M. G. Grim, S. Lincoln, J. Hardy, X. Yu, M. Picciano, K. Fechteler, et al.
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A. L. Schwarzman, N. Singh, M. Tsiper, L. Gregori, A. Dranovsky, M. P. Vitek, C. G. Glabe, P. H. St. George-Hyslop, and D. Goldgaber
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PNAS, July 6, 1999; 96(14): 7932 - 7937.
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K. Ancolio, C. Dumanchin, H. Barelli, J. M. Warter, A. Brice, D. Campion, T. Frebourg, and F. Checler
Unusual phenotypic alteration of beta  amyloid precursor protein (beta APP) maturation by a new Val-715 right-arrow Met beta APP-770 mutation responsible for probable early-onset Alzheimer's disease
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D. F. Smith, L. Whitesell, and E. Katsanis
Molecular Chaperones: Biology and Prospects for Pharmacological Intervention
Pharmacol. Rev., December 1, 1998; 50(4): 493 - 514.
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