Cited by 174Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

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Wirths, Oliver, Breyhan, Henning, Cynis, Holger, Schilling, Stephan, Demuth, Hans-Ulrich, Bayer, Thomas A.·2009·Acta Neuropathologica

DOI 10.1007/s00401-009-0557-5PMC PMC2737116

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Abstract

It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

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Authors: Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A.
Affiliations: University of Göttingen (DE)
Probiodrug (Germany) (DE)
Corresponding author: Bayer, Thomas A.
ORCID: Wirths, Oliver
Cynis, Holger
Schilling, Stephan
Demuth, Hans-Ulrich
Bayer, Thomas A.
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2009-06-23
Volume: 118
Issue: 4
Pages: 487-496
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-009-0557-5
PMC: PMC2737116
OpenAlex: W2127458156
Cited by: 174
References: 71
Citations by year: 2026: 1 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 12 · 2012: 19
FWCI: 11.49
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Acta Neuropathologica (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders: Alzheimer Forschung Initiative
European Commission (MEST-CT-2005-020013)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: pyroglutamate amyloid-beta, Alzheimer's disease, neurodegeneration, Purkinje cell degeneration, neurotoxicity, neurological deficit, amyloid precursor protein, BACE, amyloid fibril formation, cerebellum
MeSH terms: Analysis of Variance, Animals, Body Weight, Brain, Brain Diseases, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Mice, Transgenic, Nerve Degeneration, Neurons, Peptide Fragments, Phenotype, Purkinje Cells, Amyloid beta-Peptides, Cell Death, Mice

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Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

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