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