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Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases.
J Neural Transm (Vienna) 2010; 117(1):85-96JN

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.

Authors+Show Affiliations

Division of Molecular Psychiatry, Department of Psychiatry, University of Goettingen, Göttingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19823761

Citation

Wirths, Oliver, et al. "Pyroglutamate Abeta Pathology in APP/PS1KI Mice, Sporadic and Familial Alzheimer's Disease Cases." Journal of Neural Transmission (Vienna, Austria : 1996), vol. 117, no. 1, 2010, pp. 85-96.
Wirths O, Bethge T, Marcello A, et al. Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases. J Neural Transm (Vienna). 2010;117(1):85-96.
Wirths, O., Bethge, T., Marcello, A., Harmeier, A., Jawhar, S., Lucassen, P. J., ... Bayer, T. A. (2010). Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases. Journal of Neural Transmission (Vienna, Austria : 1996), 117(1), pp. 85-96. doi:10.1007/s00702-009-0314-x.
Wirths O, et al. Pyroglutamate Abeta Pathology in APP/PS1KI Mice, Sporadic and Familial Alzheimer's Disease Cases. J Neural Transm (Vienna). 2010;117(1):85-96. PubMed PMID: 19823761.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases. AU - Wirths,Oliver, AU - Bethge,Tobias, AU - Marcello,Andrea, AU - Harmeier,Anja, AU - Jawhar,Sadim, AU - Lucassen,Paul J, AU - Multhaup,Gerd, AU - Brody,David L, AU - Esparza,Thomas, AU - Ingelsson,Martin, AU - Kalimo,Hannu, AU - Lannfelt,Lars, AU - Bayer,Thomas A, Y1 - 2009/10/13/ PY - 2009/07/16/received PY - 2009/09/04/accepted PY - 2009/10/14/entrez PY - 2009/10/14/pubmed PY - 2010/3/25/medline SP - 85 EP - 96 JF - Journal of neural transmission (Vienna, Austria : 1996) JO - J Neural Transm (Vienna) VL - 117 IS - 1 N2 - 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. SN - 1435-1463 UR - https://www.unboundmedicine.com/medline/citation/19823761/Pyroglutamate_Abeta_pathology_in_APP/PS1KI_mice_sporadic_and_familial_Alzheimer's_disease_cases_ L2 - https://dx.doi.org/10.1007/s00702-009-0314-x DB - PRIME DP - Unbound Medicine ER -