Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegenerationReportar como inadecuado

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BMC Neuroscience

, 14:108

Neurobiology of disease


BackgroundPosttranslational 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 Aβ3-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 Aβ3–42 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.

ResultsExpression of truncated Aβ3–42 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.

ConclusionsETNA 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.

KeywordsETNA Pyroglutamate Aβ Glutaminyl cyclase Alzheimer’s disease TBA Neurodegeneration Neuroinflammation Striatum Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-14-108 contains supplementary material, which is available to authorized users.

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Autor: Andreas Becker - Stephanie Kohlmann - Anca Alexandru - Wolfgang Jagla - Fabio Canneva - Christoph Bäuscher - Holger Cynis


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