Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Abstract

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation.

Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core

“…When N-terminal truncation exposes a glutamic acid residue, the amino terminus of Aβ can become pyrolyzed forming a stable ring [3]. One of these post-translationally modified forms of Aβ, pyrolyzed Aβ3-x (AβpE3), is abundant in brain regions affected in AD [4, 8, 9, 15, 21, 22]. A second form of pyrolyzed Aβ, Aβ11-x (AβpE11) has received less attention, but also colocalizes with Aβ1–40/42 containing plaques in AD brain [7, 12].…”

Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation

“…In double fluorescent immunolabeling procedures, secondary antibodies were Cy2-or Cy3-coupled species-specific IgGs (Dianova). Double immunofluorescent labeling of QC and A␤ was performed as described previously (Morawski et al, 2010;Hartlage-Rübsamen et al, 2011). For histological analysis and counterstaining, sections were stained with thionine or neutral red.…”

“…pE3-A␤ is formed enzymatically during posttranslational peptide maturation via cyclization of N-terminal glutamate residues of truncated A␤ 3-x species by glutaminyl cyclase (QC)-like enzymatic activity (Schilling et al, 2004;Cynis et al, 2008). pE3-A␤ shows a higher aggregation propensity and stability, as well as a stronger tendency to seed additional aggregation of other A␤ species (He and Barrow, 1999;D'Arrigo et al, 2009;Schlenzig et al, 2009), and QC-dependent generation of pE3-A␤ has been implicated recently in AD (Schilling et al, 2008; Morawski et al, 2010). This novel hypothesis of QC-dependent pE3-A␤-mediated neurotoxicity could explain the paradox of healthy aged individuals with high amyloid plaque load but, unfortunately, has not successfully been modeled in animals thus far.…”

Original article Dendritic and spinal alterations of neurons from Edinger-Westphal nucleus in Alzheimer’s disease

“…They addressed these findings congruent to the exaggerated pupillary reaction to the cholinergic antagonist tropicamide seen in the disease. Morawski et al (2010) showed a high expression of Glutaminyl cyclase in the cholinergic nuclei of Meynert and Edinger-Westphal, related to high vulnerability of well-defined subcortical neuronal populations and their cortical projections in AD [22].…”