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

• Main Authors: O. Wirths, T. Bethge, A. Marcello, A. Harmeier, S. Jawhar, P.J. Lucassen, G. Multhaup, D.L. Brody, T. Esparza, M. Ingelsson, H. Kalimo, L. Lannfelt, T.A. Bayer
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2010
• Subjects: Arctic
• Online Access: http://hdl.handle.net/11245/1.310691

The presence of A beta(pE3) (N-terminal truncated A beta starting with pyroglutamate) in Alzheimer's disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of A beta peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down's syndrome postmortem brain tissue. Importantly, A beta(pE3) has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length A beta. We have recently shown that intraneuronal accumulation of A beta(pE3) peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in A beta(pE3), we have generated two novel monoclonal antibodies which were characterized as highly specific for A beta(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 A beta(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 A beta(pE3) plaque load with increasing age, while the density for A beta(1-x) plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of A beta are N-truncated as disease progresses, and that, A beta(pE3) positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.