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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2009

Open Access 01-12-2009 | Research article

Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptide

Authors: Rina Yamin, Cheng Zhao, Peter B O'Connor, Ann C McKee, Carmela R Abraham

Published in: Molecular Neurodegeneration | Issue 1/2009

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Abstract

Background

The abnormal accumulation of amyloid-beta peptide is believed to cause malfunctioning of neurons in the Alzheimer's disease brain. Amyloid-beta exists in different assembly forms in the aging mammalian brain including monomers, oligomers, and aggregates, and in senile plaques, fibrils. Recent findings suggest that soluble amyloid-beta oligomers may represent the primary pathological species in Alzheimer's disease and the most toxic form that impairs synaptic and thus neuronal function. We previously reported the isolation of a novel amyloid-beta-degrading enzyme, acyl peptide hydrolase, a serine protease that degrades amyloid-beta, and is different in structure and activity from other amyloid-beta-degrading enzymes.

Results

Here we report the further characterization of acyl peptide hydrolase activity using mass spectrometry. Acyl peptide hydrolase cleaves the amyloid-beta peptide at amino acids 13, 14 and 19. In addition, by real-time PCR we found elevated acyl peptide hydrolase expression in brain areas rich in amyloid plaques suggesting that this enzyme's levels are responsive to increases in amyloid-beta levels. Lastly, tissue culture experiments using transfected CHO cells expressing APP751 bearing the V717F mutation indicate that acyl peptide hydrolase preferentially degrades dimeric and trimeric forms of amyloid-beta.

Conclusion

These data suggest that acyl peptide hydrolase is involved in the degradation of oligomeric amyloid-beta, an activity that, if induced, might present a new tool for therapy aimed at reducing neurodegeneration in the Alzheimer's brain.
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Literature
1.
Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002, 297: 353-356.CrossRefPubMed
2.
Forman MS, Trojanowski JQ, Lee VM: Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med. 2004, 10: 1055-1063.CrossRefPubMed
3.
Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW: In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 1991, 563: 311-314.CrossRefPubMed
4.
Lorenzo A, Yankner BA: Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA. 1994, 91: 12243-12247.PubMedCentralCrossRefPubMed
5.
6.
Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R: Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans. 2007, 35: 1219-1223.CrossRefPubMed
7.
Glabe CC: Amyloid accumulation and pathogensis of Alzheimer's disease: significance of monomeric, oligomeric and fibrillar Abeta. Subcell Biochem. 2005, 38: 167-177.CrossRefPubMed
8.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008, 14: 837-842.PubMedCentralCrossRefPubMed
9.
Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991, 82: 239-259.CrossRefPubMed
10.
Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P: Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging. 1995, 16: 285-298.CrossRefPubMed
11.
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J: Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999, 155: 853-862.PubMedCentralCrossRefPubMed
12.
McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999, 46: 860-866.CrossRefPubMed
13.
Saido TC, Iwata N: Metabolism of amyloid beta peptide and pathogenesis of Alzheimer's disease. Towards presymptomatic diagnosis, prevention and therapy. Neurosci Res. 2006, 54: 235-253.CrossRefPubMed
14.
Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee H.-J, Hama E, Sekine-Aizawa Y, Saido TC: Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppresion leads to biochemical and pathological deposition. Nature Med. 2000, 6: 143-150.CrossRefPubMed
15.
Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ: Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. j Neurosci. 2000, 20: 1657-1665.PubMed
16.
Bernstein HG, Lendeckel U, Bukowska A, Ansorge S, Ernst T, Stauch R, Trubner K, Steiner J, Dobrowolny H, Bogerts B: Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary. J Chem Neuroanat. 2008, 35: 216-224.CrossRefPubMed
17.
Sumitomo M, Shen R, Nanus DM: Involvement of neutral endopeptidase in neoplastic progression. Biochim Biophys Acta. 2005, 1751: 52-59.CrossRefPubMed
18.
Song E-S, Hersh L: Insulysin: an allosteric enzyme as target for Alzheimer's disease. J Mol Neurosci. 2005, 25: 201-206.CrossRefPubMed
19.
Song E-S, Juliano M, Juliano L, Hersh L: Substrate activation of insulin-degrading enzyme (insulysin) a potential target for drug development. J Biol Chem. 2003, 278: 49789-49794.CrossRefPubMed
20.
Yamin R, Bagch S, Hilderbrant R, Scaloni A, Widom R, Abraham CR: Acyl peptide hydrolase, a serine proteinase isolated from conditionewd medium of neuroblastoma cells, degrades the amyloid-β peptide. J Neurochem. 2007, 100: 458-467.CrossRefPubMed
21.
Fujino T, Tada T, Hosaka T, Beppu M, Kikugawa K: Presence of oxidized protein hydrolase in human cell lines, rat tissues, and human/rat plasma. J Biochem (Tokyo). 2000, 127: 307-313.CrossRef
22.
Fujino T, Watanabe K, Beppu M, Kikugawa K, Yasuda H: Identification of oxidized protein hydrolase of human erythrocytes as acylpeptide hydrolase. Biochemica Biophysica Acta. 2000, 1478: 102-112.CrossRef
23.
Shimizu K, Fujino T, Ando K, Hayakawa M, Yasuda H, Kikugawa K: Overexpression of oxidized protein hydrolase protect COS-7 cells from oxidative stress-induced inhibition of cell growth and survival. Biochem Biophys Res Commun. 2003, 304: 766-771.CrossRefPubMed
24.
Shimizu K, Kiuchi Y, Ando K, Hayakawa M, Kikugawa K: Coordination of oxidized protein hydrolase and the proteosome in the clearance of cytotoxic denatured proteins. Biochem Biophys Res Commun. 2004, 324: 140-146.CrossRefPubMed
25.
Giardina T, Biagini A, Massey-Harroche D, Puigserver A: Distribution and subcellular localization of acylpeptide hydrolase and acylase I along the Hog gastro-intestinal tract. Biochimie. 1999, 81: 1049-1055.CrossRefPubMed
26.
Scaloni A, Barra D, Jones W, Manning J: Human Acylpeptide Hydrolase studies on its thiol groups and mechanism of action. J Biol Chem. 1994, 269: 15076-15084.PubMed
27.
28.
Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ: Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med. 2005, 11: 556-561.CrossRefPubMed
29.
Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ: Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans. 2002, 30: 552-557.CrossRefPubMed
30.
Fein JA, Sokolow S, Miller CA, Vinters HV, Yang F, Cole GM, Gylys KH: Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes. Am J Pathol. 2008, 172: 1683-1692.PubMedCentralCrossRefPubMed
31.
Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL: Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008, 7: 129-135.CrossRefPubMed
32.
Selkoe DJ: Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med. 2004, 140: 627-638.CrossRefPubMed
33.
Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, Walker D, Scheff S, McGillis JP, Rydel RE, Estus S: The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci. 2000, 20: 3937-3946.PubMed
34.
Eckman E, Reed D, Eckman C: Degradation of the Alzheimer's amyloid β peptide by endothelin-converting enzyme. J Biol Chem. 2001, 276: 24540-24548.CrossRefPubMed
35.
Farris W, Schutz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ: Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007, 171: 241-251.PubMedCentralCrossRefPubMed
36.
Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S: Abeta-degrading enzymes in Alzheimer's disease. Brain Pathol. 2008, 18: 240-252.CrossRefPubMed
37.
Blomqvist ME, Chalmers K, Andreasen N, Bogdanovic N, Wilcock GK, Cairns NJ, Feuk L, Brookes AJ, Love S, Blennow K, Kehoe PG, Prince JA: Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain. Neurobiol Aging. 2005, 26: 795-802.CrossRefPubMed
38.
Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S: Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003, 162: 313-319.PubMedCentralCrossRefPubMed
39.
Yasojima K, Akiyama H, McGeer EG, McGeer PL: Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett. 2001, 297: 97-100.CrossRefPubMed
40.
Jebanathirajah JA, Pittman JL, Thomson BA, Budnik BA, Kaur P, Rape M, Kirschner M, Costello CE, O'Connor PB: Characterization of a new qQq-FTICR mass spectrometer for post-translational modification analysis and top-down tandem mass spectrometry of whole proteins. J Am Soc Mass Spectrom. 2005, 16: 1985-1999.CrossRefPubMed
41.
O'Connor PB, Pittman JL, Thomson BA, Budnik BA, Cournoyer JC, Jebanathirajah J, Lin C, Moyer S, Zhao C: A new hybrid electrospray Fourier transform mass spectrometer: design and performance characteristics. Rapid Commun Mass Spectrom. 2006, 20: 259-266.CrossRefPubMed
42.
Metadata
Title
Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptide
Authors
Rina Yamin
Cheng Zhao
Peter B O'Connor
Ann C McKee
Carmela R Abraham
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2009
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-4-33

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