Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate-Aβ Formation

Posttranslational amyloid-beta (A beta) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified A beta species, pyroglutamate-amyloid-beta (pE3-A beta), has been described as a major constituent of A beta deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated A beta species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-A beta aggregates rapidly and is known to seed additional A beta aggregation. To directly investigate pE3-A beta toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human A beta. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating A beta and pE3-A beta deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-A beta neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3-A beta formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3-A beta levels. Hence, lowering the rate of QC-dependent posttranslational pE3-A beta formation can, in turn, lower the amount of neurotoxic A beta species in AD.