| First Author | Alexandru A | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 36 | Pages | 12790-801 |
| PubMed ID | 21900558 | Mgi Jnum | J:176575 |
| Mgi Id | MGI:5292263 | Doi | 10.1523/JNEUROSCI.1794-11.2011 |
| Citation | Alexandru A, et al. (2011) Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated A{beta} Is Induced by Pyroglutamate-A{beta} Formation. J Neurosci 31(36):12790-12801 |
| abstractText | Posttranslational amyloid-beta (Abeta) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Abeta species, pyroglutamate-amyloid-beta (pE3-Abeta), has been described as a major constituent of Abeta deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Abeta species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-Abeta aggregates rapidly and is known to seed additional Abeta aggregation. To directly investigate pE3-Abeta toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Abeta. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Abeta and pE3-Abeta deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-Abeta 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-Abeta 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-Abeta levels. Hence, lowering the rate of QC-dependent posttranslational pE3-Abeta formation can, in turn, lower the amount of neurotoxic Abeta species in AD. |
