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PLOS ONE  2011 

Multiple Insulin Degrading Enzyme Variants Alter In Vitro Reporter Gene Expression

DOI: 10.1371/journal.pone.0021429

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Abstract:

The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p = 0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5′ to the promoter (1.18 fold-change, p = 0.006) and 3′ to the reporter gene (1.29 fold change, p = 0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates Aβ degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.

References

[1]  Roher AE, Kasunic TC, Woods AS, Cotter RJ, Ball MJ, et al. (1994) Proteolysis of A beta peptide from Alzheimer disease brain by gelatinase A. Biochem Biophys Res Commun. 205. (3): pp. 1755–1761.
[2]  Backstrom JR, Lim GP, Cullen MJ, Tokes ZA (1996) Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40). J Neurosci. 16. (24): pp. 7910–7919.
[3]  Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, et al. (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 6. (2): pp. 143–150.
[4]  Hu J, Igarashi A, Kamata M, Nakagawa H (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 276. (51): pp. 47863–47868.
[5]  Kurochkin IV, Goto S (1994) Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. 345. (1): FEBS Lett. pp. 33–37.
[6]  McDermott JR, Gibson AM (1997) Degradation of Alzheimer's beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. 22. (1): Neurochem Res. pp. 49–56.
[7]  Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, et al. (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. 273. (49): J Biol Chem. pp. 32730–32738.
[8]  Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, et al. (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta -protein, and the beta -amyloid precursor protein intracellular domain in vivo. 100. (7): U S A: Proc Natl Acad Sci. pp. 4162–4167.
[9]  Bernstein HG, Ansorge S, Riederer P, Reiser M, Frolich L, et al. (1999) Insulindegrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 263(2-3): 161–164.
[10]  Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, et al. (2003) Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet 12: 23–32.
[11]  Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, et al. (1999) A full genome scan for late onset Alzheimer's disease. Hum Mol Genet 8: 237–245.
[12]  Bertram L, Blacker D, Mullin K, Keeney D, Jones J, et al. (2000) Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 290: 2302–2303.
[13]  Prince JA, Feuk L, Gu HF, Johansson B, GatzM , et al. (2003) Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Hum Mutat 22: 363–371.
[14]  Ertekin-Taner N, Allen M, Fadale D, Scanlin L, Younkin L, et al. (2004) Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat 23: 334–342.
[15]  Carrasquillo MM, Belbin O, Zou F, Allen M, Ertekin-Taner N, et al. (2010) Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease. 5. (1).PLoS One. e8764 in press.
[16]  Rockman MV, Wray GA (2002) Abundant raw material for cis-regulatory evolution in humans. 19. (11): Mol Biol Evol. pp. 1991–2004.

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