Pyroglutamate-modified amyloid-β (AβpE3) 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 AβpE3–42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of AβpE3. In this minireview, we summarize the current knowledge on AβpE3, 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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"In addition, the generation of long fatty acid–derived oligomers (LFA-os) via a prion-like mechanism (Kumar and Walter, 2011;), the increasing presence of the Aβ 43 isoform (Sandebring et al., 2013), and the Aβ-phosphorylating activity of membrane-bound or extracellular protein kinase A (Kumar and Walter, 2011;) accelerate the rate of Aβ-os assembly, reduce their proteolytic or microglia-mediated clearance, and step up their neurotoxicity. Another toxic species is pyroglutamate (pE)-Aβ 3−42 , which amounts to ∼20% of the total Aβs in AD brains, but is missing among the Aβs extracted from aged yet cognitively normal brains (Gunn et al., 2010; Jawhar et al., 2011). In AD-developing human brains, pE-Aβ 3−42 engenders pure or mixed (with other Aβs) highly toxic oligomers, the amount of which tightly correlates with the actual rate of cognitive decline (Morawski et al., 2014). "
"It has also been shown to protect proteins from degradation by aminopeptidases . In the case of amyloid b peptides, N-terminal pGlu enhances their hydrophobicity and stability , leading to accelerated aggregation . Therefore, the reduction of N-terminal pGlu through inhibition of glutaminyl cyclase is considered a new therapeutic strategy for the treatment of Alzheimer's disease . "
[Show abstract][Hide abstract]ABSTRACT: The N-termini of peptides and proteins can be subjected to highly diverse modifications, including acetylation, myristoylation, pyroglutamylation, and epimerization. These modifications affect protein stability, localization, and activity as well as alter the chemical properties of the N-terminus. Oxidative stress is known to induce the direct oxidation of amino acid side chains and peptide backbones in proteins. Alternatively, polyunsaturated fatty acids can be oxidized to lipid hydroperoxides, which further decompose to form highly reactive aldehydes such as 4-oxo-2(E)-nonenal (ONE) and 4-hydroxy-2(E)-nonenal (HNE). ONE and HNE modify various amino acid residues and induce protein cross-linking. However, there have been few studies on oxidative stress-mediated N-terminal modifications and the resulting functional changes. Our recent studies have reported several novel N-terminal modifications that result in the formation of α-ketoamide, transamination, cyclization, and epimerization. These novel N-terminal modifications are the focus of this review. We also outline recent advances in approaches for N-terminal analysis, which have been developed over the last several decades.
Full-text · Article · Dec 2015 · Drug Metabolism and Pharmacokinetics
"As a consequence of pE formation, Ab is rendered more hydrophobic , insoluble and stable toward degradation. In familial forms of AD caused by mutations in the protein PS1, pE-modified Ab represents the dominant species. Similarly, pGlu-Ab has been shown to accumulate in the course of development of sporadic ADRD. "
[Show abstract][Hide abstract]ABSTRACT: Alzheimer's disease and related dementias (ADRD) comprise several progressive and incurable neurodegenerative disorders that some have classified as amyloidosis. With increased aging of the world's population, the prevalence of the sporadic form of ADRD, which comprises over 99% of cases, continues to rise at an alarming rate. The enormous societal burdens of ADRD already rival those of the many other major chronic diseases causing premature morbidity and mortality in the USA and worldwide such as cardiovascular disease and cancer. At present, there is an insufficient totality of evidence concerning the efficacy and safety of any pharmacologic agents to delay slow progression or reduce complications of ADRD. In this context, glutaminyl cyclase (QC) inhibitors have shown some early possible evidence of efficacy with a reassuring safety profile. To reliably test the glutaminyl cyclase (QC) and any other promising hypotheses will require cogent data from large-scale randomized trials of sufficient size and duration.
Preview · Article · Oct 2015 · Expert Review of Neurotherapeutics