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


ABSTRACT:

Background

Posttranslational modifications of beta amyloid (A?) 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 A?(3-x), generating pE3-A?. Compared to unmodified A?, pE3-A? is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other A? species. To directly investigate pE3-A? formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of A?) mice expressing truncated human A?(3-42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-A? 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 A?(3-42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-A?. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-A? 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 A? levels and expression sites, while pE3-A? 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 A?. 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-A? and neuropathology strongly argues for an important role of this A? species in neurodegenerative processes in these models.

SUBMITTER: Becker A 

PROVIDER: S-EPMC3850634 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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<h4>Background</h4>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 an  ...[more]

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