Schilling, S. et al. Glutaminyl cyclase inhibition attenuates pyroglutamate A and Alzheimer's disease-like pathology. Nature Med. 14, 1106-1111

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Nature medicine (Impact Factor: 27.36). 11/2008; 14(10):1106-11. DOI: 10.1038/nm.1872
Source: PubMed


Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.

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Available from: Manfred Windisch, Oct 08, 2015
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    • "Moreover, massive accumulation of intraneuronal A␤ 42 is observed, which has recently come to be considered as a remarkable pathological cause of AD [36] [37] [38] [39]. I.p. injection of QCI in 5XFAD was chosen as the route of administration because PBD150, a prominent QCI, showed its inhibitory effect when it was orally administrated to mice, indicating that PBD150 penetrates the bloodbrain barrier (BBB) [21]. Since the QCI used in this study is a derivative of PBD150 [2], we assumed that it is able to penetrate the BBB. "
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    ABSTRACT: Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid-β peptides (Aβ) are generated from amyloid-β precursor protein by consecutive catalysis by β- and γ-secretases. Diversely modified forms of Aβ have been discovered, including pyroglutamate Aβ (N3pE-42 Aβ). N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length Aβ. A previous study suggested that N3pE-42 Aβ formation is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE-42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation, namely modulation of γ-secretase activity.
    Journal of Alzheimer's disease: JAD 01/2015; 43(3):797-807. DOI:10.3233/JAD-141356 · 4.15 Impact Factor
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    • "The QC-mediated conversion of N-terminal glutamate resulting in the formation of pathogenic pGlu-A␤ peptides has been shown to proceed optimally at mildly acidic conditions (Schilling et al., 2004). It has been shown that the inhibition of QC activity reduces the generation of pGlu-A␤ peptides in vitro (Buchholz et al., 2006; Cynis et al., 2006) and in experimental animals in vivo (Schilling et al., 2008). Based on these observations pGlu-A␤ emerged as a novel target for treatment of A␤ pathology and the inhibition of QC enzymatic activity is regarded as a rational therapeutic approach in AD (Saido, 1998; He and Barrow, 1999; Russo et al., 2002; Saido and Iwata, 2006; Schilling et al., 2006). "
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    ABSTRACT: Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) from glutamine precursors at the N-terminus of a number of peptide hormones, neuropeptides and chemokines. This post-translational modification stabilizes these peptides, protects them from proteolytical degradation or is important for their biological activity. However, QC is also involved in a pathogenic pGlu modification of peptides accumulating in protein aggregation disorders such as Alzheimer's disease and familial Danish and familial British dementia. Its isoenzyme (isoQC) was shown to contribute to aspects of inflammation by pGlu-modifying and thereby stabilizing the monocyte chemoattractant protein CCL2. For the generation of respective animal models and for pharmacological treatment studies the characterization of the mouse strain and brain region-specific expression of QC and isoQC is indispensible. In order to address this issue, we used enzymatic activity assays and specific antibodies to detect both QC variants by immunohistochemistry in nine different mouse strains. Comparing different brain regions, the highest enzymatic QC/isoQC activity was detected in ventral brain, followed by cortex and hippocampus. Immunohistochemical stainings revealed that QC/isoQC activity in cortex mostly arises from isoQC expression. For most brain regions, the highest QC/isoQC activity was detected in C3H and FVB mice, whereas low QC/isoQC activity was present in CD1, SJL and C57 mice. Quantification of QC- and isoQC-immunoreactive cells by unbiased stereology revealed a higher abundance of isoQC- than of QC-immunoreactive neurons in Edinger-Westphal nucleus and in substantia nigra. In the locus coeruleus, however, there were comparable densities of QC- and of isoQC-immunoreactive neurons. These observations are of considerable importance with regard to the selection of appropriate mouse strains for the study of QC/isoQC relevance in mouse models of neurodegeneration and neuroinflammation and for the testing of therapeutical interventions in these models.
    International Journal of Developmental Neuroscience 05/2014; DOI:10.1016/j.ijdevneu.2014.05.008 · 2.58 Impact Factor
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    • "Cynis et al. [14] showed that the pyroGlu-formation of MCP-1 depends on glutaminyl cyclase (QC) activity. The same group has also provided strong evidence that Glu-3 of Aβ is pyroglutamated by QC [86]. Genetic ablation of the glutaminyl cyclase iso-enzymes QC or isoQC revealed a major role of isoQC for pyroGlu-MCP-1 formation and monocyte infiltration [14]. "
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    ABSTRACT: Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer's disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer's patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides.
    Acta Neuropathologica 05/2014; 127(6). DOI:10.1007/s00401-014-1287-x · 10.76 Impact Factor
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