Open Access Highly Accessed Research article

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration

Andreas Becker12, Stephanie Kohlmann2, Anca Alexandru2, Wolfgang Jagla2, Fabio Canneva1, Christoph Bäuscher2, Holger Cynis3, Reinhard Sedlmeier2, Sigrid Graubner2, Stephan Schilling3, Hans-Ulrich Demuth23* and Stephan von Hörsten1*

Author Affiliations

1 Department of Experimental Therapy, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany

2 Ingenium Pharmaceuticals GmbH, 82152 Martinsried, Germany

3 Probiodrug AG, Biocenter, Weinbergweg 22, 06120 Halle (Saale), Germany

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BMC Neuroscience 2013, 14:108  doi:10.1186/1471-2202-14-108

Published: 1 October 2013



Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3–42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice.


Expression of truncated Aβ(3–42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss.


ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models.

ETNA; Pyroglutamate Aβ; Glutaminyl cyclase; Alzheimer’s disease; TBA; Neurodegeneration; Neuroinflammation; Striatum