BMC Neuroscience | |
Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration | |
Stephan von Hörsten3  Hans-Ulrich Demuth2  Stephan Schilling2  Sigrid Graubner1  Reinhard Sedlmeier1  Holger Cynis2  Christoph Bäuscher1  Fabio Canneva3  Wolfgang Jagla1  Anca Alexandru1  Stephanie Kohlmann1  Andreas Becker1  | |
[1] Ingenium Pharmaceuticals GmbH, 82152 Martinsried, Germany;Probiodrug AG, Biocenter, Weinbergweg 22, 06120 Halle (Saale), Germany;Department of Experimental Therapy, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany | |
关键词: Striatum; Neuroinflammation; Neurodegeneration; TBA; Alzheimer’s disease; Glutaminyl cyclase; Pyroglutamate Aβ; ETNA; | |
Others : 1140041 DOI : 10.1186/1471-2202-14-108 |
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received in 2012-10-21, accepted in 2013-09-18, 发布年份 2013 | |
【 摘 要 】
Background
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.
Results
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.
Conclusions
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.
【 授权许可】
2013 Becker et al.; licensee BioMed Central Ltd.
【 预 览 】
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