title: Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases.
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.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, University of Goettingen, Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Tobias
authors.initials: T
authors.lastname: Bethge
authors.forename: Andrea
authors.initials: A
authors.lastname: Marcello
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.forename: Sadim
authors.initials: S
authors.lastname: Jawhar
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: David L
authors.initials: DL
authors.lastname: Brody
authors.forename: Thomas
authors.initials: T
authors.lastname: Esparza
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D058255:Protease Nexins; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011761:Pyrrolidonecarboxylic Acid