Article

Prion-Like Behavior and Tau-dependent Cytotoxicity of Pyroglutamylated β-Amyloid

Department of Biology, University of Virginia, Charlottesville, Virginia 22904, USA.
Nature (Impact Factor: 42.35). 05/2012; 485(7400):651-5. DOI: 10.1038/nature11060
Source: PubMed

ABSTRACT Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.

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    • "In this sense, an increasing body of evidence suggests a clinical and biochemical intersection among prionopathies, tauopathies and synucleinopathies [12] [29]. In addition, interactions between PrP and Tau [43] and PrP and A42 oligomers [21] have been described, while prion-like spreading of pathological proteins seems to be a common mechanism, having been described in animal models of -synuclein [26], -amyloid [30] and Tau [7]. Furthermore, the deposition of phosphorylated Tau, -amyloid and -synuclein has been reported in prion diseases of various etiologies [41]. "
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    ABSTRACT: AimsCreutzfeldt-Jakob disease (CJD) is a rapid progressive neurological disease leading to dementia and death. Prion biomarkers are altered in the cerebrospinal fluid (CSF) of CJD patients, but the pathogenic mechanisms underlying these alterations are still unknown. The present study examined prion biomarker levels in the brain and CSF of sporadic CJD (sCJD) cases and their correlation with neuropathological lesion profiles.Methods The expression levels of 14-3-3, Tau, phospho-Tau and α-synuclein were measured in the CSF and brain of sCJD cases in a subtype- and region-specific manner. In addition, the activity of prion biomarker kinases, the expression levels of CJD hallmarks and the most frequent neuropathological sCJD findings were analysed.ResultsPrion biomarkers levels were increased in the CSF of sCJD patients; however, correlations between mRNA, total protein and their phosphorylated forms in brain were different. The observed downregulation of the main Tau kinase, GSK3, in sCJD brain samples may help to explain the differential phospho-Tau/Tau ratios between sCJD and other dementias in the CSF. Importantly, CSF biomarkers levels do not necessarily correlate with sCJD neuropathological findings.InterpretationPresent findings indicate that prion biomarkers levels in sCJD tissues and their release into the CSF are differentially regulated following specific modulated responses, and suggest a functional role for these proteins in sCJD pathogenesis.
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    • "These pGlu-A␤ peptides are more neurotoxic, hydrophobic and resistant to aminopeptidase degradation compared to unmodified A␤ peptides and thus accumulate in AD brain (Saido, 1998; Russo et al., 2002). This A␤ variant also acts as a seeding peptide species during plaque formation and co-aggregates with unmodified A␤ peptides (He and Barrow, 1999; Schilling et al., 2006; Nussbaum et al., 2012). Different analytical methods demonstrated that N-terminally truncated and pGlu-modified A␤ represents a major A␤ peptide variant in plaques of AD subjects (Saido et al., 1995; Kuo et al., 1997; Russo et al., 1997; Harigaya et al., 2000; Liu et al., 2006; Piccini et al., 2005; Portelius et al., 2010). "
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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 · 2.92 Impact Factor
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    • "This kind of progression mechanism could also explain the pattern observed in other neurodegenerative diseases. Supporting this hypothesis, a prion-like behaviour of an amyloid was characterized in Alzheimer’s disease in a recent study from Nussbaum and colleagues [158]. "
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    05/2014; 3:10. DOI:10.1186/2047-9158-3-10
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