Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration

BMC Neuroscience

Stephan von Hörsten³  Hans-Ulrich Demuth²  Stephan Schilling²  Sigrid Graubner¹  Reinhard Sedlmeier¹  Holger Cynis²  Christoph Bäuscher¹  Fabio Canneva³  Wolfgang Jagla¹  Anca Alexandru¹  Stephanie Kohlmann¹  Andreas Becker¹ 

[1] Ingenium Pharmaceuticals GmbH, 82152 Martinsried, Germany;Probiodrug AG, Biocenter, Weinbergweg 22, 06120 Halle (Saale), Germany;Department of Experimental Therapy, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany

关键词: Striatum;    Neuroinflammation;    Neurodegeneration;    TBA;    Alzheimer’s disease;    Glutaminyl cyclase;    Pyroglutamate Aβ;    ETNA;   

Others  :  1140041
DOI  :  10.1186/1471-2202-14-108

 received in 2012-10-21, accepted in 2013-09-18,  发布年份 2013

【 摘 要 】

Background

Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3–42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice.

Results

Expression of truncated Aβ(3–42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss.

Conclusions

ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models.

【 授权许可】

   
2013 Becker et al.; licensee BioMed Central Ltd.

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【 参考文献 】

• [1]Schilling S, Manhart S, Hoffmann T, Ludwig HH, Wasternack C, Demuth HU: Substrate specificity of glutaminyl cyclases from plants and animals. Biol Chem 2003, 384(12):1583-92.
• [2]Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU: Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett 2004, 563(1–3):191-6.
• [3]Seifert F, Schulz K, Koch B, Manhart S, Demuth HU, Schilling S: Glutaminyl cyclases display significant catalytic proficiency for glutamyl substrates. Biochemistry 2009, 48(50):11831-3.
• [4]Saido TC: Alzheimer’s disease as proteolytic disorders: anabolism and catabolism of beta-amyloid. Neurobiol Aging 1998, 19(1 Suppl):S69-75.
• [5]Tekirian TL, Yang AY, Glabe C, Geddes JW: Toxicity of pyroglutaminated amyloid beta-peptides 3(pE)-40 and −42 is similar to that of A beta1-40 and −42. J Neurochem 1999, 73(4):1584-9.
• [6]Saido TC: Involvement of polyglutamine endolysis followed by pyroglutamate formation in the pathogenesis of triplet repeat/polyglutamine-expansion diseases. Med Hypotheses 2000, 54(3):427-9.
• [7]Vidal R, Frangione B, Rostagno A, Mead S, Révész T, Plant G, Ghiso J: A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 1999, 399(6738):776-81.
• [8]Ghiso JA, Holton J, Miravalle L, Calero M, Lashley T, Vidal R, Houlden H, Wood N, Neubert TA, Rostagno A, Plant G, Revesz T, Frangione B: Systemic amyloid deposits in familial British dementia. J Biol Chem 2001, 276(47):43909-14.
• [9]Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, Funke SA, Schilling S, Demuth HU: Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 2009, 48(29):7072-8.
• [10]Schlenzig D, Rönicke R, Cynis H, Ludwig HH, Scheel E, Reymann K, Saido T, Hause G, Schilling S, Demuth HU: N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt Hippocampal long-term Potentiation. J Neurochem 2012, 121(5):774-84.
• [11]Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S: Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 1995, 14(2):457-66.
• [12]Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001, 81(2):741-66.
• [13]Zhang H, Ma Q, Zhang YW, Xu H: Proteolytic processing of Alzheimer’s β-amyloid precursor protein. J Neurochem 2012, 120(Suppl 1):9-21.
• [14]Cynis H, Rahfeld JU, Stephan A, Kehlen A, Koch B, Wermann M, Demuth HU, Schilling S: Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J Mol Biol 2008, 379(5):966-80.
• [15]He W, Barrow CJ: The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta. Biochemistry 1999, 38(33):10871-7.
• [16]D’Arrigo C, Tabaton M, Perico A: N-terminal truncated pyroglutamyl beta amyloid peptide Abetapy3- 42 shows faster aggregation kinetics than the full-length Abeta1-42. Biopolymers 2009, 91(10):861-73.
• [17]Alexandru A, Jagla W, Graubner S, Becker A, Bäuscher C, Kohlmann S, Sedlmeier R, Raber KA, Cynis H, Rönicke R, Reymann KG, Petrasch-Parwez E, Hartlage-Rübsamen M, Waniek A, Rossner S, Schilling S, Osmand AP, Demuth HU, von Hörsten S: Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation. J Neurosci 2011, 31(36):12790-801.
• [18]Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA: Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol 2009, 118(4):487-96.
• [19]Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, Demuth HU, Blennow K, Wirths O, Bayer TA: Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. J Biol Chem 2012, 287(11):8154-62.
• [20]Lüthi A, Van der Putten H, Botteri FM, Mansuy IM, Meins M, Frey U, Sansig G, Portet C, Schmutz M, Schröder M, Nitsch C, Laurent JP, Monard D: Endogenous serine protease inhibitor modulates epileptic activity and Hippocampal long-term Potentiation. J Neurosci 1997, 17(12):4688-99.
• [21]Friedman TC, Loh YP, Cawley NX, Birch NP, Huang SS, Jackson IM, Nillni EA: Processing of prothyrotropin-releasing hormone (Pro-TRH) by bovine intermediate lobe secretory vesicle membrane PC1 and PC2 enzymes. Endocrinology 1995, 136(10):4462-72.
• [22]Cynis H, Schilling S, Bodnár M, Hoffmann T, Heiser U, Saido TC, Demuth HU: Inhibition of glutaminyl cyclase alters pyroglutamate formation in mammalian cells. Biochim Biophys Acta 2006, 1764(10):1618-25.
• [23]Siebert PD, Chenchik A, Kellogg DE, Lukyanov KA, Lukyanov SA: An improved PCR method for walking in uncloned genomic DNA. Nucleic Acids Res 1995, 23:1087-1088.
• [24]Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ, Martin JE: Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 1997, 8(10):711-3.
• [25]Karl T, Pabst R, von Hörsten S: Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol 2003, 55(1):69-83.
• [26]Paxinos G, Franklin KB: The mouse brain in stereotaxic coordinates. San Diego: Elsevier Academic; 2008.
• [27]Carpenter AE, Jones TR, Lamprecht MR, Clarke C, Kang IH, Friman O, Guertin DA, Chang JH, Lindquist RA, Moffat J, Golland P, Sabatini DM: CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 2006, 7(10):R100. BioMed Central Full Text
• [28]Nillni EA, Sevarino KA: The biology of pro-thyrotropin-releasing hormone-derived peptides. Endocr Rev 1999, 20(5):599-648.
• [29]Spongr VP, Flood DG, Frisina RD, Salvi RJ: Quantitative measures of hair cell loss in CBA and C57BL/6 mice throughout their life spans. J Acoust Soc Am 1997, 101(6):3546-53.
• [30]Keithley EM, Canto C, Zheng QY, Fischel-Ghodsian N, Johnson KR: Age-related hearing loss and the ahl locus in mice. Hear Res 2004, 188(1–2):21-8.
• [31]Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, König S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT: Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 2011, 71(5):833-44.
• [32]Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Rönicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU, Bloom GS: Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 2012, 485(7400):651-5.
• [33]Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P: DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 2004, 44:269-96.
• [34]Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O: Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 2010, 33(1):e29-40. 196
• [35]Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L: Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 1995, 270(47):28257-67.
• [36]Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L: High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000, 20(11):4050-8.
• [37]McGowan E, Eriksen J, Hutton M: A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 2006, 22(5):281-9.
• [38]Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR: Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 1995, 58(2):192-200.
• [39]Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, McKinzie DL, Fienberg AA, Nomikos GG, Greengard P: Diverse psychotomimetics act through a common signaling pathway. Science 2003, 302(5649):1412-5.
• [40]Jellinger KA: Neurodegenerative Erkrankungen (ZNS) - Eine aktuelle Übersicht. J Neurol Neurochir Psychiatr 2005, 6(1):9-18.
• [41]Miller BR, Walker AG, Fowler SC, von Hörsten S, Riess O, Johnson MA, Rebec GV: Dysregulation of coordinated neuronal firing patterns in striatum of freely behaving transgenic rats that model Huntington’s disease. Neurobiol Dis 2010, 37(1):106-13.
• [42]Zuccato C, Valenza M, Cattaneo E: Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 2010, 90(3):905-81.
• [43]Bateup HS, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier DJ, Fisone G, Nestler EJ, Greengard P: Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci USA 2010, 107(33):14845-50.