Human Molecular Genetics, 2000, Vol. 9, No. 16 2383-2394
© 2000 Oxford University Press
Transcriptional regulation of Alzheimer’s disease genes: implications for susceptibility
Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Universiteitsplein 1, B-2610 Antwerpen, Belgium
Received 19 June 2000; Accepted 6 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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In recent years, important progress has been made in uncovering genes implicated in Alzheimer’s disease (AD). Three causal genes have been identified in which mutations cause familial presenile AD: the amyloid precursor protein gene and the presenilin 1 and 2 genes. Additionally, the
4 allele of the apolipoprotein E gene was shown to be a major risk factor for AD. Despite the genetic heterogeneity, all of these genes work through a common mechanism, i.e. increasing the amount and deposition of the amyloid ß peptide (Aß) in brain triggering AD-related neuronal degeneration. Therefore, the levels of Aß and of the factors involved in its production and deposition are important in the neuropathogenesis of AD. Regulation of transcription of AD genes might therefore be an important player in the neurodegenerative process. In this review, we describe the major features of transcriptional regulation of the known AD genes and the implications of variable expression levels on susceptibility to AD. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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Alzheimer’s disease (AD) is a neurodegenerative disorder of the brain characterized by neuronal loss, extensive deposition of amyloid ß peptide (Aß) in the brain parenchyma and in vessel walls, and the appearance of neuronal inclusions of abnormally phosphorylated tau. The regions that are most affected are the hippocampus and cerebral cortex. Clinically, AD patients show a gradually progressive decline in memory and cognitive functions that is diagnosed on neurological examination, neuropsychological testing and neuroimaging. Among the dementias, AD is the most frequent, with 70% of cases affected. The prevalence of AD increases with age, with 40% of the population older than 85 years affected (1). Apart from aging per se, two other well defined risk factors are gender and family history of AD (2). The genetic etiology of AD is complex, with both genetic and environmental factors influencing the expression of the phenotype. Nevertheless, in a small percentage (<1%) of AD cases the disease is inherited as a fully penetrant monogenic trait in an autosomal dominant manner. In all these cases, the disease onset is before the age of 65 years, i.e. presenile AD or early-onset AD (EOAD). These monogenic AD families have been instrumental in the identification of AD genes using the positional cloning approach. At least four genetic loci that confer inherited susceptibility have been identified to date. Characteristics of these genes are summarized in Table 1. The first causative gene identified for EOAD is the amyloid precursor protein gene (APP) (3) on chromosome 21q21.2 (4), encoding a single membrane-spanning protein (5–9). Full-length APP is metabolized rapidly by two major pathways in all cells. In many cells, the most prominent pathway is the constitutive pathway where
-secretase cleaves the Aß sequence (10), producing N-truncated Aß peptides. Neurons, however, have an intrinsic tendency to metabolize APP along the amyloidogenic pathway (11–13), in which sequential cleavage by ß- and 
-secretases releases full-length Aß peptides. Whereas ß-secretase cleaves highly specifically, -secretase cleaves less specifically, leading to either a 40 amino acid peptide (Aß40) or a 42 amino acid isoform (Aß42) (14,15). All eight AD-related APP mutations detected to date are located near the secretase cleavage sites and have been demonstrated to interfere with APP processing, leading to increased secretion of Aß42. This Aß42 peptide has been shown, at least in vitro, to aggregate more rapidly into fibrils (16) and was claimed to be the earliest and most abundant Aß peptide in amyloid deposits (17–19). Recent theories propose that Aß deposits or partially aggregated soluble Aß trigger a neurotoxic cascade, thereby causing neurodegeneration and AD (20,21). As a result, Aß and, in particular, Aß42 were assigned a pivotal role in AD pathogenesis.
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The most frequently mutated EOAD gene is presenilin 1 (PSEN1), located on chromosome 14q24.3 (22–24). Based on homology studies, the third causal EOAD gene, presenilin 2 (PSEN2), was isolated and mapped to chromosome 1q42.3 (25,26). The PSEN genes encode highly homologous integral membrane proteins with eight putative transmembrane domains (27–30). To date, >60 PSEN1 and 4 PSEN2 mutations have been identified in EOAD patients, scattered over the entire coding region of the genes (http://molgen-www.uia.ac.be/ADMutations/ ). Both in vitro and in vivo, PSEN mutations lead to increased Aß42 production, suggesting a role for PSEN in the processing of APP (31–45). Together, these findings led to the hypothesis of a gain of function for mutant PSEN (20) and provided further evidence for the central role of Aß42 in AD pathogenesis. PSENs have also been shown to be death substrates undergoing caspase cleavage during apoptosis (46–48). Although the role of apoptosis in neuronal cell death in AD remains to be proven, AD-linked PSEN mutations, as well as decreased expression of PSEN1 and overexpression of PSEN2 (46), result in apoptosis (49). However, the homology with SEL-12 of Caenorhabditis elegans suggested a possible role for PSEN in NOTCH signaling (50). Further evidence was provided by the study of embryonically lethal PSEN1-deficient mice, which show abnormal somite segmentation, a phenotype shared with NOTCH1-deficient mice (51,52). Moreover, mutations in other genes involved in NOTCH signaling also lead to central nervous system (CNS) disorders with onset ages in adulthood (53).
In addition to the three causative genes, the 4 allele of the apolipoprotein E gene (APOE) on chromosome 19 was identified as a genetic risk factor for both EOAD (54,55) and late-onset AD (LOAD) (56–58). The risk associated with the 4 allele is dose dependent, which is reflected in the increased risk and decreased onset age with the number of 4 alleles (59). Several observations indicated that APOE 4 is also involved in increased Aß deposition. It was shown that APOE promotes Aß fibril formation in vitro (60). Also, APOE 4 has a higher binding affinity for Aß than has APOE 3 (56,61), possibly making Aß insoluble and therefore more prone to deposition. Although these in vitro data are controversial, AD patients homozygous for APOE 4 have indeed been shown to have more Aß deposits than APOE 3 homozygotes (62). Also, it was shown that APOE 4 influences the onset age of EOAD patients carrying an AD-related APP mutation but not that of PSEN1 mutation carriers (63).
Since mutations in the causal EOAD genes explain <1% and APOE 4 <20% of all AD cases (22,64,65), it is clear that other genetic factors are involved in AD pathogenesis. Variation in the regulatory regions of APP (66,67), PSEN1 (22,68,69) and APOE (70–73) have been suggested to contribute to susceptibility to AD. In this review, we will discuss the importance of expression levels of known AD genes and the implications of variations in their regulatory regions for susceptibility to AD.
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GENE EXPRESSION AND REGULATION OF TRANSCRIPTION |
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APP is expressed in a variety of tissues, with the highest expression in neuronal cells of the CNS (6,74–77). APP expression can be induced by a variety of agents such as growth hormones and cytokines (9,11,78–86) and by stress conditions (87–89). Up-regulation (90,91) of APP promoter activity corroborates with mRNA expression studies (82,92), suggesting a major role for the APP promoter in specific APP expression.
The control mechanisms of APP gene expression have been subject to extensive studies. The APP promoter contains numerous putative binding sites for regulatory transcription factors (Table 2) (93–97). However, deletion mapping of the APP promoter demonstrated that <100 bp upstream of the transcriptional start site (TSS) are sufficient for high levels of expression in numerous cell types (98–100). This proximal promoter region is devoid of a functional TATA box, and transcription initiation is regulated by a strong initiator element (Inr) surrounding the major TSS +1 (Fig. 1A) (9,95,97,101). Mutations within and immediately upstream of Inr lead to altered use of multiple TSSs and reduce transcriptional activity. Both Inr and the upstream element (UE) are associated with DNase I-protected domains, suggesting sequence-specific binding of nuclear factors (101).
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APP promoter activation is covered mainly by two GC-rich elements (Table 2, Fig. 1A) (100). The –93/–82 fragment (APBß) contributes at least 70% to APP promoter activity in both neuronal and non-neuronal cells and was shown to bind the CCCTC-binding factor (CTCF), a known regulator of c-myc expression implicated in the promotion of apoptosis (Table 2, Fig. 1A) (102,103). The remaining APP promoter activity is accounted for mainly by the –65/–41 fragment (APB
) and is mediated by binding of stimulating protein 1 (SP1) and the upstream stimulatory factor (USF), member of the c-Myc-related family of DNA-binding proteins (99,104–106). Recently, an interaction model for APP transcriptional activity based on DNA looping was presented. In this model, a novel SP1-like protein forms a homodimer tethering the USF and 5'-flanking SP1 sites, and the upstream AP-1 site with flanking GC-rich motif (Fig. 2, Table 2) (98,107).
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Transcriptional activation of APP can also be mediated by heat shock factor-1 (HSF-1) binding to the heat shock element (HSE) at position –317 (Table 2, Fig. 1A) (88). HSF-1 activation is induced by numerous stress factors, including hypoxia, decreased pH, elevated Ca2+, decreased ATP and exposure to reactive species. It was also reported recently that members of the NF-
B/Rel family can specifically recognize two identical sequences at –1837/–1822 and –2250/–2241, in the distal promoter region of APP, referred to as APPB sites (108). These sites were shown to interact specifically with a complex containing the p50 subunit of the NF-B family that is constitutively expressed in neurons and acts as a positive regulator of gene expression in cells of neuronal origin (109). The distal APP promoter also harbors at least one negative regulator of transcription, the upstream regulatory element (URE) between –2257 and –2234, binding an unknown transcription factor (TF), expressed in a restricted number of cell types and different regions of the human brain (110,111).
Not only are the structure and expression pattern of APP highly conserved between species (112,113), but the promoter regions of rodents and primates are also highly homologous to that of the human APP (
80%) (93,94,114). They all have a high GC content, lack typical TATA and CAAT boxes and share nearly all of the above-described TF-binding sites (Table 2), suggesting a major role for these TFs in APP regulation in vivo (93,94,99,114).
Like APP, the PSENs are ubiquitously expressed, although they display markedly tissue-specific transcriptional differences. In brain, both PSEN1 transcripts of 2.7 and 7.5 kb are present at relatively high levels, whereas only one PSEN2 transcript (2.3 kb) can be detected at relatively low levels (24,26, 115,116). Both PSENs are expressed primarily in neurons and to a lesser extent in glial cells (117–127). The PSEN1 5'-untranslated region (UTR) is contained within four exons, with the first two exons (1A and 1B) being alternatively transcribed (Table 1) (128,129). Multiple TSSs have been reported to date, with the major exon 1A TSSs designated +1(P1) and (P2) (Fig. 1B) (129,130).
Deletion mapping of the PSEN1 promoter delineated the most active fragment from –118 to +178 relative to +1(P1), in both neuronal and non-neuronal cells (131). The sequence in this region contains >70% GC, lacks a TATA box but contains transcriptionally active GC boxes around positions –70, –50 and +20 (Fig. 1B), binding SP1-like TFs. The crucial PSEN1 promoter element is located between –22 and –6 and controls >90% of PSEN1 promoter activity. This region contains a binding motif for Ets proteins at –12 (Fig. 1B), and altering the core sequence results in a drastic decrease in promoter activity, by interfering with TF binding. In neuronal cells, the PSEN1 promoter binds an Ets-1/2 protein. Both Ets-1 and Ets-2 are widely expressed in different tissues but are differentially regulated (132,133). Ets-2 is present at high levels in adult brain, including post-mitotic neurons. Ets-1 is particularly abundant in the CNS during specific developmental stages (133). Another Ets family member, Elk-1, has also been shown to be expressed in brain where it is localized exclusively to neurons (134). Which members of the Ets family are able to activate PSEN1 transcription in vivo is not clear. Sequences (+107 to +178) downstream from the TSS also contain major cis-elements, controlling 
80% of total PSEN1 promoter activity. Collectively, these data indicate that sequences upstream and downstream of the TSS each control >80% of promoter activity, indicating the importance of protein–protein interactions between TFs binding to upstream and downstream cis-elements.
Preliminary data on murine PSEN1 promoter activity and in situ hybridization suggest that PSEN1 is expressed and transcribed preferentially in neurons. The structure and expression of PSEN1 are highly conserved between mice and human. Multiple mRNA transcripts, originating from TSSs of alternatively transcribed first exons, have been reported for both species. Reporter gene analysis showed that both TSSs are most probably controlled by one single promoter spanning the +1 position of exon 1A (130). In human, only one exon 1B transcript has been reported so far; therefore, it is difficult to conceive how exon 1B transcription can be driven from the same promoter as the abundant exon 1A transcripts, as described for the mouse transcripts. Hence, it is possible that transcription from the human exon 1B is controlled by its own promoter or at least by exon 1B-specific cis-elements, possibly located downstream of +178. Until now, no data on functional cis-elements controlling transcription from human PSEN1 exon 1B have been reported.
In the regulatory region, maximal similarity is found in the –39/+117 sequence of the mouse PSEN1 promoter region. The +20 GC box (SP1) and the –12 Ets motif are strictly conserved, and reporter gene analysis indicated that this region contributes to the neuron-preferred promoter activity (130). The mouse sequence upstream of position –39 differs significantly from the human sequences. Absence of long stretches of sequence homology is one of the main problems in promoter recognition and it is conceivable that more functional cis-elements, although not located at the corresponding positions, are shared between the mouse and human PSEN1 promoter. Furthermore, sequences from –22 to +178, which confer >80% of human PSEN1 promoter activity, coincide with the region of high homology with the mouse promoter. Also, the major human +1 TSS is located only eight nucleotides downstream of the mouse TSS (130,131), emphasizing the importance of this region for the function of the promoter in both species.
Despite the striking similarities between PSEN2 and PSEN1 in genomic structure, alternative transcripts and use of multiple TSSs (116,135,136), there is little homology in the 5'-flanking region, and the first two exons of PSEN2, although alternatively transcribed, are not mutually exclusive (116). There are two distinct cis-elements regulating transcription from the predicted TSS. PSEN2 basal promoter activity resides between –403 and +13, a TATA-less, GC-rich region containing numerous putative AP-2 and SP1 sites (137). In this region, a functional nerve growth factor (NGF)-responsive element that mediates PSEN2 promoter activation following NGF treatment also resides. The observed 2-fold up-regulation by NGF confirmed the predicted involvement of PSENs in neuronal differentiation (138). Whether the AP-2 or SP1 sites clustered in this region or another as yet unidentified cis-element is responsible for the NGF responsiveness is not yet clear. Further deletion analysis provided evidence for the existence of a second PSEN2 promoter located in intron 1, directing transcription from the start sites in exon 2, though no functional elements have been identified so far.
APOE is expressed in a variety of tissues and cell types and its expression is highly regulated by nutritional, hormonal, tissue- and cell-specific factors, and intracellular cholesterol levels (139,140). In contrast to the causal AD genes, the 5'-flanking sequence of APOE harbors a functional TATA box (141). Multiple general and specific cis-elements have been mapped to the APOE promoter (Table 2, Fig. 1C) (140). The proximal GC box binds SP1 and is required for maximum transcriptional activity (142). Three non-specific enhancer elements, active in both neuronal and non-neuronal cells (143), were identified. Two of these, upstream regulatory elements 1 (URE1) and 2 (URE2), reside in the proximal promoter region and one resides in the first intron, the intron regulatory element 1 (IRE1). The dominant regulatory sequence in URE1 is located from –161 to –141 and is termed the positive element for transcription (PET). This fragment binds at least two TFs, one of which is SP1. Although SP1 is the only protein required for enhancer activity of PET, a second as yet unknown protein competes with SP1, in this way possibly negatively regulating APOE expression (142). A fourth regulatory domain in the APOE promoter, URE3, binds the 300 kDa URE3-binding protein, but needs further characterization (144).
In astrocytic cells, the activity of the proximal promoter of APOE is up-regulated synergistically by cAMP and retinoic acid (RA), which is mediated by two AP-2 sites located in the proximal promoter (145). cAMP mimics the changes occurring in reactive gliosis (146,147) and RA is a potent morphogenetic agent on the developing nervous system and a known regulator of AP-2 expression (148). It is therefore reasonable to presume that the observed synergistic effect of cAMP and RA on the APOE promoter is probably due to an RA-promoted increase in AP-2, followed by a post-transcriptional activation of AP-2 mediated by cAMP (148,149). More tissue-specific cis-elements identified at present seem to reside downstream of APOE, with a potential brain-specific transcriptional activator in the APOE–APOCI intergenic region (150–154).
The 5' upstream region of rodent APOE is homologous to human APOE up to 200 bp upstream of the TSS (155,156), with the TATA box, the proximal GC box and URE3 at corresponding positions (Table 2) (141,156,157).
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PROMOTER VARIATIONS AND TRANSCRIPTIONAL ACTIVITY |
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TOPABSTRACTINTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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Screening for mutations in the –802/+268 APP promoter fragment in sporadic, and familial EOAD and LOAD cases did not reveal any AD-specific mutation (158–161). However, a C
G transversion was detected at position –209 in both affected and unaffected subjects (Table 3) (161). Although this variation is not unique for AD, it may have an effect on APP transcriptional activity associated with AD. Since the number of patients and controls was small and the individual analyses covered only parts of the APP promoter, one cannot yet exclude the existence of AD-related variations in the APP promoter altering transcriptional activity. Recent sib-pair analyses suggested that genetic variability at the APP locus may contribute to risk for LOAD (66,67). It is obvious that a systematic screening of the APP regulatory sequences in extended AD populations is necessary.
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Besides the amount of full-length APP available, the amount and activity of APP processing factors also influence the production of the amyloidogenic Aß42. Since PSENs were assigned a pivotal role in APP processing, altered PSEN expression due to variations in regulatory regions is considered a risk factor for AD. Genetic association studies in a population-based EOAD case–control sample showed association of the single nucleotide polymorphism (SNP) –48C
T with EOAD (Table 3) (68). Systematic screening of 3 kb of the PSEN1 upstream region in the same population revealed, in addition to –48C/T (22), four novel polymorphisms (–1789G/A, –2154G/A, –2319Tn and –2823I/D), two of which (–2154G/A and –2823I/D) were also shown to be associated with increased risk for EOAD (Table 3). Linkage disequilibrium allowed for the identification of an EOAD risk haplotype (–48C/–2154G/–2823D). Additionally, two potentially AD-related mutations (–280CG and –2818AG) were identified (Table 3) (69). The effect of –280CG and –48CT on the transcriptional activity of PSEN1 was studied in a transient transfection system. Luciferase reporter gene analysis demonstrated a neuron-specific 30% decrease in promoter activity for the –280G mutant and a neuron-specific 50% decrease in promoter activity for the –48C risk allele, which in homozygous individuals can lead to a critical decrease in PSEN1 expression. Notably, the genetic association of –48C with EOAD was explained by an over-representation of the CC genotype in EOAD patients. These studies provide evidence that increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of PSEN1 in neuronal cells due to differential binding of nuclear proteins (69,162,163). These data suggest that the increased risk for EOAD associated with PSEN1 may result from decreased expression levels of the PSEN1 protein. Although PSEN2 has also been shown to be involved in APP processing, and changes in its expression levels might be important in AD pathology, no association was found with AD and no PSEN2 promoter variations have been reported to date.
It was shown that the relative APOE 4 mRNA level is increased in AD compared with controls, and it was suggested that genetic variability in the neuronal expression of APOE contributes to disease risk (70). Multiple studies suggested that genetic variability in the regulatory region of APOE may modulate the risk associated with the APOE 4 isoform. The first variation detected in the APOE regulatory region was a CG transversion at position +113 in the intron 1 enhancer element (IE1), although no statistically significant association independent of APOE 4 could be detected (Table 3) (164). In a population-based study, three SNPs (–491AT, –427TC and –219TG alias Th1E47cs) and two heterozygous mutations (–557CT and –456CT) were identified (Table 3) (71,73). Reporter gene analysis and electrophoretic mobility shift assays (EMSAs) demonstrated that the three SNPs alter transcriptional activity of the APOE promoter due to differential binding of TFs (71,72). For all three SNPs, genetic association with AD, independent of APOE 4, was reported (71–73). Although several studies attempted to confirm this association, most reported either absence of association or association due to linkage disequilibrium with APOE 4 (114,165–172). However, population-based differences of APOE 4 frequencies, giving rise to differences in relative risk for AD, have been documented previously (173,174). It is therefore conceivable that there is a wide variation in relative risk for AD associated with APOE promoter polymorphisms.
In vivo studies demonstrated that the deleterious effect on disease risk of both the –219T and –491A risk alleles correlated with an increased expression of the 4 allele in brain (175). Later it was shown that the –491AA risk genotype is associated with increased levels of APOE in plasma, independently of APOE 4 or AD status, though more pronounced in AD patients (176). These data provide evidence that, in addition to the qualitative effect of the APOE 2/3/4 isoforms on risk for AD, the quantitative variation of expression of these isoforms due to functional APOE promoter variations is a key determinant in AD development.
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IMPLICATIONS OF VARIABLE GENE EXPRESSION ON AD PATHOGENESIS |
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TOPABSTRACTINTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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The most favored hypothesis suggests a pivotal role for increased Aß42 secretion in AD pathology. Since the amount of APP and of factors involved in its processing are crucial for this elevation, it is conceivable that the transcriptional regulation of their genes plays an important role in AD pathology. A number of studies indicate that the amount of APP mRNA is indeed increased in AD brains (177–181). Moreover, trisomy 21 in Down syndrome (DS) patients leads to a 4- to 5-fold overexpression of APP, resulting in a 50 year decrease in onset age of AD in DS patients compared with the normal population (182). These results imply that a fundamental component of the molecular etiology of AD may lie in the expression of APP, its biogenesis and turnover, since the induction of the pathway leading to Aß production will depend on the amount of APP present.
Since overlapping cis-elements are known to be important for differential gene expression (183–185), the presence of overlapping SP1- and USF-binding sites in the APP promoter suggests that two different and independent regulatory pathways for APP expression might exist, one mediated by SP1 and the other by USF (104). SP1 has been shown to be ubiquitously expressed, however, with a substantial variation in different cell types and during development (186). The low levels of SP1 detected in different brain regions suggest that USF might also contribute substantially to the high expression of APP in neuronal cells, which was confirmed by EMSA with nuclear extracts from rat brain showing binding to USF but not to SP1. A number of factors have been reported that are able to influence SP1 activity in certain cell types, in this way leading to preferred usage of one pathway (187,188). Therefore, a deregulated overexpression of APP in brain might simply be caused by a local increase in SP1 activity.
Additionally, AD brains exhibit numerous features which indicate that neurons affected by AD exist under conditions of stress. Since APP expression is regulated by stress factors, one can speculate that APP may be one of the genes coordinately modulated in brain in response to situations that require a defensive reaction. Stress-induced overexpression of APP can then lead to increased Aß production. It is therefore conceivable that an imbalance between different regulatory pathways for APP expression, caused by a variation in a functional cis-element or by altered expression levels of TFs in specific brain regions, might be a risk factor for AD.
During aging, the expression of PSENs decreases (120), and an even more significant decrease in PSEN has been reported in neurons from brain areas adversely affected by AD (189,190). In contrast, astrocytes reacting to neurodegeneration express elevated levels of PSEN (189,191). Several lines of evidence indicate that PSEN1 is closely linked to the -secretase processing of APP and that decreased expression (<50%) and mutations in PSEN1 lead to increased secretion of Aß42 (20,192). Small changes in PSEN expression levels can have major implications for APP processing and AD pathology.
Additionally, PSENs were shown to be death substrates undergoing caspase cleavage during apoptosis (46–48,193). Although the role of apoptosis in neuronal cell death in AD remains to be proven, it is interesting that PSEN2 overexpression and AD-linked mutations in both PSENs can shift conventional PSEN cleavage towards caspase cleavage (46), whereas a reduction of PSEN1 results in apoptosis (49). Regardless of the hypothesis on AD pathology, it is clear that expression of both PSENs is highly regulated and that mutations or variations leading to altered expression can easily be imagined to have major effects on PSEN functioning.
APOE was suggested to be involved in the repair process following nerve injury. It was shown that APOE has an effect on neurite morphogenesis of cultured neurons, where APOE 3 reduces the amount of neurite branching and promotes neurite extension, whereas APOE 4 does not (194,195). In brain, APOE synthesis takes place in astrocytes (196,197) and is increased dramatically after nerve injury (198–200). The reactive gliosis in AD brains involves a series of morphological and biochemical changes in activated astrocytes (201), including up-regulation of APOE mRNA levels which is mediated by AP-2 (202). Further determination of the molecular mechanisms involved in the regulation of APOE synthesis in brain is a matter of greatest importance, considering the possible roles of this protein in processes of repair in the pathogenesis of AD (56,59). Here, special attention needs to be drawn to mechanisms of differential expression of the different APOE isoforms.
Although it is clear that expression levels of AD genes are important in AD etiology, little is known about their specific regulation. Studying the effect of variations in regulatory elements and their corresponding TFs will contribute to our understanding of the disease process.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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The promoters of all three causal EOAD genes, APP and PSEN1/2, show characteristics of promoters of housekeeping genes. All lack a functional TATA box and show a very high GC content presenting multiple potential SP1 sites, known to be involved in transcription initiation and regulation of TATA-less promoters (137). APP, PSEN1 and PSEN2 are ubiquitously expressed, though with a tightly controlled differential regulation depending on tissue and cell type, developmental stage and environmental factors. Interestingly, all these proteins are synthesized predominantly in neurons of the CNS. This highly controlled regulation implicates the presence of specific regulatory elements mediating transcriptional activity, though only few of these have been described to date. The regulation of APOE is extremely complex, with multiple general and specific positive and negative cis-elements. In brain, APOE is expressed in astrocytes and is probably involved in neuronal regeneration processes.
It is well documented that single nucleotide changes in a promoter region may affect transcriptional activity mediated by TFs (203,204), either by directly altering a TF-binding site or by changing the structure of DNA, thereby affecting the access of TFs. Multiple studies provided evidence that altered expression levels of APP, PSENs and the different isoforms of APOE are involved in AD pathology, suggesting a role for transcriptional regulation in the disease process. Variations in functional regulatory elements can therefore be considered risk factors for AD when altering gene expression. To date, promoter variations in PSEN1 and APOE have been shown to be associated with increased risk for AD. Functional data suggested that the increased risk for AD could be explained by the effect of the promoter variations on transcriptional levels of both genes either by decreasing the levels of total expression (PSEN1) or by differentially influencing the expression levels of different isoforms (APOE). Further analysis of the transcriptional regulation of AD genes and of variations in their regulatory regions will lead to more insight into AD etiology.
Multiple factors, both genetic and environmental, underlie the etiology of complex diseases like AD. It is therefore conceivable that an interplay of discrete transcriptional changes of different genes can influence disease processes. Analysis of regulatory regions of disease genes and the effect of variations on gene regulation is therefore very important for the elucidation of complex disease processes.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +32 3 8202601; Fax: +32 3 8202541; Email: cvbroeck@uia.ua.ac.be
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REFERENCES |
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TOPABSTRACTINTRODUCTIONGENE EXPRESSION AND REGULATION...PROMOTER VARIATIONS AND...IMPLICATIONS OF VARIABLE GENE...CONCLUSIONSREFERENCES |
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