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
Source: PubMed


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). "
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    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
    • "While A plaques are poor correlates for the clinical symptomatology in AD and Down syndrome, soluble oligomers are suggested to be good predictors for synaptic loss [54], neurofibrillary tangles [55], and clinical phenotype [56] [57]. They exert more stability, are resistant to degradation, show more aggregation propensity and cellular toxicity, and gain considerable attention as potential players in the pathology of AD due to their abundance in AD brain [17] [58]. The presence of pyroGlu-3 peptides has been reported as an important component of plaque depositions in patients with AD [59] [60]. "
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    ABSTRACT: Autosomal dominant familial Alzheimer's disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson's disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD-related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation.
    Journal of Alzheimer's disease: JAD 09/2014; 44(1). DOI:10.3233/JAD-141524 · 4.15 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 [120] (Fig. 1). Aβ peptides can undergo racemization [121, 122], isomerization [123], phosphorylation [124, 125], oxidation [126, 127], non-enzymatic glycation [128], and pyroglutamylation [129]. Post-translational oxidation of Met35 affects fibril flexibility within Aβ plaques [127]. "
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    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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