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Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated A? is induced by pyroglutamate-A? formation.

ABSTRACT: Posttranslational amyloid-? (A?) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified A? species, pyroglutamate-amyloid-? (pE3-A?), has been described as a major constituent of A? deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated A? species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-A? aggregates rapidly and is known to seed additional A? aggregation. To directly investigate pE3-A? toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human A?. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating A? and pE3-A? deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-A? 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? 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? levels. Hence, lowering the rate of QC-dependent posttranslational pE3-A? formation can, in turn, lower the amount of neurotoxic A? species in AD.

SUBMITTER: Alexandru A

PROVIDER: S-EPMC6623394 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation.

Alexandru Anca A Jagla Wolfgang W Graubner Sigrid S Becker Andreas A Bäuscher Christoph C Kohlmann Stephanie S Sedlmeier Reinhard R Raber Kerstin A KA Cynis Holger H Rönicke Raik R Reymann Klaus G KG Petrasch-Parwez Elisabeth E Hartlage-Rübsamen Maike M Waniek Alexander A Rossner Steffen S Schilling Stephan S Osmand Alexander P AP Demuth Hans-Ulrich HU von Hörsten Stephan S

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110901 36

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 direc ...[more]

PMID: 21900558

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Project description:Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-? precursor protein (APP). Products of APP processing - N-terminally truncated amyloid-? peptide (N-tr-A?) species - are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress. Because abnormally high levels of N-tr-A? are detected in only a fraction of neurons in the prefrontal cortex, we applied immunocytochemical staining and confocal microscopy in autopsy brain material from idiopathic and chromosome 15q11.2-q13 duplication (dup-15) autism to measure the load of N-tr-A? in the cells and synapses and to identify the subpopulation of neurons affected by these pathophysiological processes. The peptides accumulated in autism are N-terminally truncated; therefore, we produced a new antibody against A? truncated at N-terminal amino acid 11 modified to pyroglutamate to evaluate the presence and distribution of this peptide species in autism. We also quantified and characterized the oligomerization patterns of the A?-immunoreactive peptides in autism and control frozen brain samples. We provide morphological evidence, that in idiopathic and dup-15 autism, accumulation of N-tr-A? with and without pyroglutamate-11 modified N-terminus affects mainly the parvalbumin-expressing subpopulation of GABAergic neurons. N-tr-A? peptides are accumulated in neurons' cytoplasm and nucleus as well as in GABAergic synapses. A? peptides with both C-terminus 40 and 42 were detected by immunoblotting in frozen cortex samples, in the form of dimers and complexes of the molecular sizes of 18-24kD and 32-34kD. We propose that deposition of N-tr-A? specifically affects the functions of the parvalbumin-expressing GABAergic neurons and results in a dysregulation of brain excitatory-inhibitory homeostasis in autism. This process may be the target of new therapies.

Dataset Information

Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated A? is induced by pyroglutamate-A? formation.

Publications

Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation.

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