Research ReportPromoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease
Introduction
The etiology of Alzheimer's disease (AD) is complex and apolipoprotein E (APOE) is the only gene that has been characterized definitely as a risk factor for AD. Identification of other risk factors is therefore of great importance in the elucidation of AD etiology. Recently, several linkage studies show that susceptibility to late-onset AD is linked to a large region on chromosome 10q (Myers and Goate, 2001; and Tanzi and Bertram, 2001). The gene encoding for insulin degrading enzyme (IDE) is one of the candidate genes in this area for AD as it is involved in the catabolism of amyloid beta protein (Aβ) (Bertram et al., 2000). Cerebral accumulation of Aβ is believed to be crucial in AD pathogenesis. The actual amount of neurotoxic Aβ in the brain is determined by Aβ production through amyloid precursor protein (APP) processing and Aβ degradation and clearance. Aβ-degrading proteases could regulate the cerebral levels of the peptide, and IDE is exactly one of these Aβ-degrading proteases (Ling et al., 2003).
IDE is a 110-kDa neutral thiol-metalloendopeptidase that was first identified as the major proteolytic enzyme for insulin (Ogawa et al., 1992). It is ubiquitously expressed, with its highest expression in the liver, testes, muscle and the brain (Kuo et al., 1993). Several short peptides have been shown to serve as the substrates of IDE, including insulin (Kirschner and Goldberg, 1983), insulin-like growth factors I and II (Misbin and Almira, 1989), amylin (Bennett et al., 2000), Aβ (Kurochkin and Goto, 1994, McDermott and Gibson, 1997, Mukherjee et al., 2000; and Qiu et al., 1998) and others, many of which have similar secondary structure and amyloidogenic character (Bennett et al., 2000; and Kurochkin, 2001). Among the substrates of IDE, insulin and amylin are related to the pathogenesis of type 2 diabetes, while Aβ is involved in AD pathology (Mukherjee et al., 2000, Qiu et al., 1997, Vekrellis et al., 2000, Qiu and Folstein, 2006; and Sudoh et al., 2002). These substrates compete with each other to be degraded by IDE in vivo. If the insulin level increases in the brain, it would inhibit IDE to degrade Aβ effectively as a result.
Several association studies using a single nucleotide polymorphism (SNP) approach have investigated the relationship between IDE and AD (Abraham et al., 2001, Bian et al., 2004, Boussaha et al., 2002, Edland et al., 2003, Ertekin-Taner et al., 2004, Nowotny et al., 2005, Prince et al., 2003; and Sakai et al., 2004), and found that some variations were related to late-onset AD in the absence of the ApoEε4 allele. In other case-control studies, genetic variations in the IDE increased both the risk for developing AD and the severity of the disease (Prince et al., 2003). However, the results of these genetic studies remain controversial, with some studies unable to identify an association with AD (Abraham et al., 2001, Boussaha et al., 2002; and Sakai et al., 2004). Variants in these transcriptional regulation sequences may alter the transcriptional activity (Lv et al., 2008, Sander et al., 2005; and Heijmans et al., 2002) specially under certain conditions. To explore the pathogenesis of sporadic AD (SAD), it is reasonable to examine genetic variants in these sequences. In the current study we aimed to systematically screen the proximal promoter of IDE, detect potential variants, and then determine whether these variants are associated with SAD, genetically and functionally.
Section snippets
IDE promoter polymorphisms
We sequenced the 1377 bp fragment of the proximal promoter of IDE in 40 individuals and found three polymorphisms which are −1002T/G (rs3758505), −179T/C (rs4646953) and −51C/T (rs4646954). Definitive genotyping of these markers and APOE polymorphism were performed using restriction enzyme digestion in 357 SAD patients and 331 controls. Distributions of these genotypes were in Hardy–Weinberg equilibrium in all subjects. The allele and genotype distributions in two groups are shown in Table 1.
Discussion
IDE expression levels may directly affect the extracellular concentration of Aβ in brain tissue. Research in genetically manipulated mice revealed that the lack of IDE protein or enzyme activity caused the increase of Aβ levels and plaque depositions (Farris et al., 2003, Farris et al., 2004; and Miller et al., 2003), whereas enhanced IDE activity in the IDE and APP double transgenic mice decreased their brain Aβ levels, and prevented the formation of AD pathology (Leissring et al., 2003).
In
Subjects
The study group consisted of 357 SAD patients (152 men and 205 women; mean age = 70.3 ± 9.8 years; mean age at onset = 62.2 ± 4.3 years). Probable AD was diagnosed clinically according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). None of these patients reported a family history of AD. The control group consisted of 331 healthy subjects (126 men and 205 women; mean age = 66.6 ±
Acknowledgments
We gratefully acknowledge the technique supports and helpful discussions of our colleagues and collaborators. This work was supported by the National Key Technology R&D Program in the Eleventh Five-year Plan Period (2006BAI02B01), the National Basic Research 973 Program (2006CB500700), the Beijing Natural Science Foundation (7071004), and the Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality. This work was
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