Pyroglutamate Amyloid- (A ): A Hatchet Man in Alzheimer Disease
Department of Molecular Psychiatry, Georg-August-University Göttingen, University Medicine Göttingen, 37075 Göttingen, Germany.Journal of Biological Chemistry (Impact Factor: 4.57). 09/2011; 286(45):38825-32. DOI: 10.1074/jbc.R111.288308
Pyroglutamate-modified amyloid-β (Aβ(pE3)) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of Aβ(pE3-42) show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of Aβ(pE3). In this minireview, we summarize the current knowledge on Aβ(pE3), discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.
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- "The modification of peptides by pGlu gained considerable interest due to its presence at the N-terminus of amyloid peptides such as ABri and Aβ (Jawhar et al., 2011a; Saul et al., 2013). In principle, the pGlu-modification has been shown to alter the biophysical properties of peptides by increasing their hydrophobicity, which may, in turn, increase the aggregation propensity, toxicity and stability against degradation by aminopeptidases (Jawhar et al., 2011b). "
ABSTRACT: Secretory peptides and proteins are frequently modified by pyroglutamic acid (pE, pGlu) at their N-terminus. The modification is catalyzed by the glutaminyl cyclases QC and isoQC. Here, we decipher the roles of the isoenzymes by characterization of IsoQC-/- mice. These mice show a significant reduction of glutaminyl cyclase activity in brain and peripheral tissue, suggesting ubiquitous expression of the isoQC enzyme. An assay of substrate conversion in vivo reveals impaired generation of the pGlu-modified C-C chemokine ligand 2 (CCL2, MCP-1) in isoQC-/- mice. The formation was also impaired in primary neurons, which express significant levels of QC. Interestingly, however, the formation of the neuropeptide hormone thyrotropin-releasing hormone (TRH), assessed by immunohistochemistry and hormonal analysis of hypothalamic-pituitary-thyroid axis was not affected in isoQC-/-, which contrasts to QC-/-. Thus, the results reveal differential functions of isoQC and QC in the formation of the pGlu-peptides CCL2 and TRH. Substrates requiring extensive prohormone processing in secretory granules, such as TRH, are primarily converted by QC. In contrast, protein substrates such as CCL2 appear to be primarily converted by isoQC. The results provide a new example, how subtle differences in subcellular localization of enzymes and substrate precursor maturation might influence pGlu-product formation.Biological Chemistry 09/2015; DOI:10.1515/hsz-2015-0192 · 3.27 Impact Factor
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- "The in vivo Aβ pool not only contains different Aβ peptide lengths but also comprises post-translationally modified Aβ  (Fig. 1). Aβ peptides can undergo racemization [121, 122], isomerization , phosphorylation [124, 125], oxidation [126, 127], non-enzymatic glycation , and pyroglutamylation . Post-translational oxidation of Met35 affects fibril flexibility within Aβ plaques . "
ABSTRACT: The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer's disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo "pool" of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD.Cellular and Molecular Life Sciences CMLS 05/2014; 71(18). DOI:10.1007/s00018-014-1634-z · 5.81 Impact Factor
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- "The " modified amyloid hypothesis " now suggests that intraneuronal Aβ accumulation precedes the formation of extracellular plaques and other pathological events in the brains of AD patients (Wirths et al., 2004). Next to the numerous variants of Aβ 1–42 oligomers there is substantial evidence that N-terminal truncated peptides play a key role in AD (Jawhar et al., 2011). Besides Aβ peptides starting with an aspartate at position 1, a variety of different N-truncated Aβ peptides have been identified in AD brains. "
ABSTRACT: One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.Frontiers in Aging Neuroscience 04/2014; 6:75. DOI:10.3389/fnagi.2014.00075 · 4.00 Impact Factor
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