Pyroglutamate amyloid ß (Aß) 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

ABSTRACT 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 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 · 5.86 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. "
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    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 · 2.84 Impact Factor
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    • "Aβ species ending at position 43 have shown to be potently amyloidogenic and abundant [12]. Additionally to the full length Aβ peptides starting with N-terminal aspartate at position 1, different N-truncated isoforms have been demonstrated to be as abundant as toxic due to their capacity to rapidly form stable aggregates [13]. Not much is known about the N-terminally truncated Aβ5-x present in the amyloid pathology of AD brains. "
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    ABSTRACT: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (Abeta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Abeta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Abetax-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Abetax-42 species have been pointed as crucial players in AD etiology, the Abeta5-x isoforms have not received much attention. The present study is the first to show immunohistochemical evidence of Abeta5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Abeta5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Abeta5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Abeta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Abeta5-x. Different degrees of Abeta5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Abeta5-x, these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Abeta5-x-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Abeta5-x peptides and operating in a divergent way in the late and early onset forms of the disease.
    Molecular Neurodegeneration 04/2014; 9(1):13. DOI:10.1186/1750-1326-9-13 · 5.29 Impact Factor
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