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Cited by 107Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases

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Wirths, Oliver, Bethge, Tobias, Marcello, Andrea, Harmeier, Anja, Jawhar, Sadim, Lucassen, Paul J., Multhaup, Gerd, Brody, David L., Esparza, Thomas, Ingelsson, Martin, Kalimo, Hannu, Lannfelt, Lars, Bayer, Thomas A.·2010·Journal of Neural Transmission
DOI 10.1007/s00702-009-0314-xPMC PMC2789212
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Abstract

The presence of Abeta(pE3) (N-terminal truncated Abeta starting with pyroglutamate) in Alzheimer's disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Abeta peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down's syndrome postmortem brain tissue. Importantly, Abeta(pE3) has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Abeta. We have recently shown that intraneuronal accumulation of Abeta(pE3) peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in Abeta(pE3), we have generated two novel monoclonal antibodies which were characterized as highly specific for Abeta(pE3) peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases. Abundant plaques positive for Abeta(pE3) were present in patients with sporadic AD and familial AD including those carrying mutations in APP (arctic and Swedish) and PS1. Interestingly, in APP/PS1KI mice we observed a continuous increase in Abeta(pE3) plaque load with increasing age, while the density for Abeta(1-x ) plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Abeta are N-truncated as disease progresses, and that, Abeta(pE3) positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.

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Fig. 1 Plaque staining with pGlu Aβ (AβpE3) antibodies in frontal cortex in sporadic AD brain. Plaques staining with antibody 4G8 (a), pGlu Aβ antibodies 2-48 (b) and 1-57(c); but no staining in plaque-free healthy control tissue (d, 2-48 staining). Scale bar 100 μm
Fig. 1 Plaque staining with pGlu Aβ (AβpE3) antibodies in frontal cortex in sporadic AD brain. Plaques staining with antibody 4G8 (a), pGlu Aβ antibodies 2-48 (b) and 1-57(c); but no staining in plaque-free healthy control tissue (d, 2-48 staining). Scale bar 100 μmCC BY-NC · PubMed Central
Fig. 2 Binding specificity of pGlu Aβ (AβpE3) antibodies. (a) Biacore analysis revealed that pGlu antibodies 2-48 (b) and 1-57 specifically bind to AβpE3-38, not to Aβ3-38 and Aβ1-38. (c) The commercial antibody Aβ[N] recognizes only Aβ1-38, not Aβ3-38 or AβpE3-38. (d) 2-48 and 1-57 recognize Aβ3p(E)-42, but not Aβ1-42, Aβ3-42, or Aβ11p(E)-42 under these conditions. Lane 1 Aβ1-42, Lane 2 Aβ3-42, Lane 3 Aβ11p(E)-42, Lane 4 Aβ3p(E)-42. 10 ng per well of each peptide was loaded on 3 separate 12% Bis–Tris gels, transferred to nitrocellulose and blotted with 1 μg/ml of each primary antibody. 2-48 and 1-57 recognize Aβ3p(E)-42, Aβ1-42, Aβ3-42, or Aβ11p(E)-42 under these conditions
Fig. 2 Binding specificity of pGlu Aβ (AβpE3) antibodies. (a) Biacore analysis revealed that pGlu antibodies 2-48 (b) and 1-57 specifically bind to AβpE3-38, not to Aβ3-38 and Aβ1-38. (c) The commercial antibody Aβ[N] recognizes only Aβ1-38, not Aβ3-38 or AβpE3-38. (d) 2-48 and 1-57 recognize Aβ3p(E)-42, but not Aβ1-42, Aβ3-42, or Aβ11p(E)-42 under these conditions. Lane 1 Aβ1-42, Lane 2 Aβ3-42, Lane 3 Aβ11p(E)-42, Lane 4 Aβ3p(E)-42. 10 ng per well of each peptide was loaded on 3 separate 12% Bis–Tris gels, transferred to nitrocellulose and blotted with 1 μg/ml of each primary antibody. 2-48 and 1-57 recognize Aβ3p(E)-42, Aβ1-42, Aβ3-42, or Aβ11p(E)-42 under these conditionsCC BY-NC · PubMed Central
Fig. 3 Plaque load analysis in APP/PS1KI mice. Plaque load was quantified at 2, 6 and 10 months of age (n = 5, female mice only). a–c Aβ[N] an antibodies specific for position 1 of Aβ showed a peak at six and a decline at 10 months of age. d–f 4G8 recognizing Aβ 17-24 showed an increase between 2 and 6 month of age, while at 10 months the plaque load did not increase any more. Analysis with the Aβ pyroglutamate (AβpE3) antibodies 2-48 (g–i) and 1-57 (j–l) demonstrated a continuous increase. Scale bar 200 μm
Fig. 3 Plaque load analysis in APP/PS1KI mice. Plaque load was quantified at 2, 6 and 10 months of age (n = 5, female mice only). a–c Aβ[N] an antibodies specific for position 1 of Aβ showed a peak at six and a decline at 10 months of age. d–f 4G8 recognizing Aβ 17-24 showed an increase between 2 and 6 month of age, while at 10 months the plaque load did not increase any more. Analysis with the Aβ pyroglutamate (AβpE3) antibodies 2-48 (g–i) and 1-57 (j–l) demonstrated a continuous increase. Scale bar 200 μmCC BY-NC · PubMed Central
Fig. 4 Staining pattern in frontal cortex of sporadic and familial AD brain. Upper panel showing the staining pattern in a sporadic AD case using 4G8 (Aβ 17-24), 2-48 (pGlu Aβ) and Aβ[N] (specific for Aβ at position 1) (a–c). While the staining pattern of 4G8 and 2-48 is comparable, there is no staining with Aβ[N]. Middle panel comparable levels of plaque load with all three antibodies in a FAD case with the Swedish mutation. Note abundant vessel staining with all three antibodies (d–f). Lower panel the same is true for the staining pattern in a case with the arctic mutation; however, Aβ[N] staining is less abundant (g–i). Scale bar 200 μm
Fig. 4 Staining pattern in frontal cortex of sporadic and familial AD brain. Upper panel showing the staining pattern in a sporadic AD case using 4G8 (Aβ 17-24), 2-48 (pGlu Aβ) and Aβ[N] (specific for Aβ at position 1) (a–c). While the staining pattern of 4G8 and 2-48 is comparable, there is no staining with Aβ[N]. Middle panel comparable levels of plaque load with all three antibodies in a FAD case with the Swedish mutation. Note abundant vessel staining with all three antibodies (d–f). Lower panel the same is true for the staining pattern in a case with the arctic mutation; however, Aβ[N] staining is less abundant (g–i). Scale bar 200 μmCC BY-NC · PubMed Central

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Metadata

Authors
Wirths, O., Bethge, T., Marcello, A., Harmeier, A., Jawhar, S., Lucassen, P. J., Multhaup, G., Brody, D. L., Esparza, T., Ingelsson, M., Kalimo, H., Lannfelt, L., & Bayer, T. A.
Affiliations
  • University of Göttingen (DE)
  • Freie Universität Berlin (DE)
  • University of Amsterdam (NL)
  • Washington University in St. Louis (US)
  • Uppsala University (SE)
Corresponding author
Bayer, Thomas A.
ORCID
Venue
Journal of Neural Transmission
Publisher
Springer Science and Business Media LLC
Published
2009-10-13
Volume
117
Issue
1
Pages
85-96
ISSN
  • 0300-9564 (ISSN-L)
  • 1435-1463
DOI
10.1007/s00702-009-0314-x
PMC
PMC2789212
OpenAlex
W2097338951
Cited by
106
References
65
Citations by year
2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 13 · 2014: 7 · 2013: 10 · 2012: 14
FWCI
8.61
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Journal of Neural Transmission (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
European Commission (MEST-CT-2005-020013)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
pyroglutamate amyloid-beta, Alzheimer's disease, amyloid plaques, amyloid-beta aggregation, amyloid beta degradation, APP mutations, PS1 mutations, monoclonal antibodies, neuronal loss, aging, familial Alzheimer's disease, sporadic Alzheimer's disease
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Middle Aged, Mutation, Peptide Fragments, Pyrrolidonecarboxylic Acid, Receptors, Cell Surface, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Presenilin-1, Plaque, Amyloid, Protease Nexins

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