In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 36 ( 2011-09-07), p. 12790-12801
Abstract:
Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3–Aβ), has been described as a major constituent of Aβ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Aβ species by glutaminyl cyclase (QC; QPCT ) and/or its isoenzyme (isoQC; QPCTL ), pE3–Aβ aggregates rapidly and is known to seed additional Aβ aggregation. To directly investigate pE3–Aβ toxicity in vivo , we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Aβ. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Aβ and pE3–Aβ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3–Aβ 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–Aβ 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–Aβ levels. Hence, lowering the rate of QC-dependent posttranslational pE3–Aβ formation can, in turn, lower the amount of neurotoxic Aβ species in AD.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.1794-11.2011
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2011
detail.hit.zdb_id:
1475274-8
SSG:
12