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

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