Dementias - Original Article

Journal of Neural Transmission

, Volume 117, Issue 1, pp 85-96

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Oliver WirthsAffiliated withDivision of Molecular Psychiatry, Department of Psychiatry, University of GoettingenNEURAD International Alzheimer Graduate School
  • , Tobias BethgeAffiliated withInstitute of Chemistry and Biochemistry, Free University of BerlinNEURAD International Alzheimer Graduate School
  • , Andrea MarcelloAffiliated withDivision of Molecular Psychiatry, Department of Psychiatry, University of GoettingenNEURAD International Alzheimer Graduate School
  • , Anja HarmeierAffiliated withInstitute of Chemistry and Biochemistry, Free University of Berlin
  • , Sadim JawharAffiliated withDivision of Molecular Psychiatry, Department of Psychiatry, University of GoettingenNEURAD International Alzheimer Graduate School
  • , Paul J. LucassenAffiliated withCenter for Neuroscience, Swammerdam Institute of Life Sciences, University of AmsterdamNEURAD International Alzheimer Graduate School
  • , Gerd MulthaupAffiliated withInstitute of Chemistry and Biochemistry, Free University of BerlinNEURAD International Alzheimer Graduate School
  • , David L. BrodyAffiliated withDepartment of Neurology, Washington University
  • , Thomas EsparzaAffiliated withDepartment of Neurology, Washington University
    • , Martin IngelssonAffiliated withDepartment of Public Health and Caring Sciences, Rudbeck Laboratory, University of Uppsala
    • , Hannu KalimoAffiliated withDepartment of Public Health and Caring Sciences, Rudbeck Laboratory, University of Uppsala
    • , Lars LannfeltAffiliated withDepartment of Public Health and Caring Sciences, Rudbeck Laboratory, University of Uppsala
    • , Thomas A. BayerAffiliated withDivision of Molecular Psychiatry, Department of Psychiatry, University of GoettingenNEURAD International Alzheimer Graduate SchoolDivision of Molecular Psychiatry, Department of Psychiatry, University of Goettingen Email author 

Abstract

The presence of AβpE3 (N-terminal truncated Aβ starting with pyroglutamate) in Alzheimer’s disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Aβ peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down’s syndrome postmortem brain tissue. Importantly, AβpE3 has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Aβ. We have recently shown that intraneuronal accumulation of AβpE3 peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in AβpE3, we have generated two novel monoclonal antibodies which were characterized as highly specific for AβpE3 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 AβpE3 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 AβpE3 plaque load with increasing age, while the density for Aβ1-x plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Aβ are N-truncated as disease progresses, and that, AβpE3 positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.

Keywords

Transgenic mice Arctic mutation Swedish mutation Presenilin-1 mutation Sporadic Alzheimer’s disease Pyroglutamate Abeta Biacore Antibody specificity