Abstract
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 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.ResultsExpression 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.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.
Highlights
Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties
In case of Alzheimer’s disease (AD), Aβ is generated in the amyloidogenic pathway, a multi-step cleavage process of the amyloid precursor protein (APP) [12,13] and pyroglutamate Aβ is formed enzymatically during posttranslational peptide maturation via cyclization of N-terminal glutamate residues of truncated Aβ(3-×) species by QClike enzymatic activity [2,14]
ETNA mice were intercrossed with tg mice overexpressing human QC to further investigate the role of QC in pE3-Aβ formation in vivo
Summary
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. The formation of pyroglutamate (pGlu, pE) at the Nterminus of various peptides and proteins is catalyzed by glutaminyl cyclase (QC, QPCT) and its isoenzyme (isoQC, QPCTL). In case of AD, Aβ is generated in the amyloidogenic pathway, a multi-step cleavage process of the amyloid precursor protein (APP) [12,13] and pyroglutamate Aβ (pE3-Aβ) is formed enzymatically during posttranslational peptide maturation via cyclization of N-terminal glutamate residues of truncated Aβ(3-×) species by QClike enzymatic activity [2,14]. The characteristic properties of pE3-Aβ, high aggregation propensity and stability, as well as a strong tendency to seed further aggregation of other Aβ species [9,15,16], result in an Aβ form with increased toxicity
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