β-amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes

Della C. David, Lars M. Ittner, Peter Gehrig, Denise Nergenau, Claire Shepherd, Glenda Halliday, Jürgen Götz*

*Corresponding author for this work

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by Aβ peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Aβ plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting β-amyloid peptide 1-42 (Aβ42) into brains of P301L tau mutant mice. In cell culture, Aβ42 induces filamentous tau aggregates. To understand which processes are disrupted by Aβ42 in the presence of tau aggregates, we applied comparative proteomics to Aβ42- treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Aβ42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Aβ42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Aβ42- mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.

Original languageEnglish
Pages (from-to)6566-6577
Number of pages12
JournalProteomics
Volume6
Issue number24
DOIs
Publication statusPublished - 1 Dec 2006
Externally publishedYes

Keywords

  • Alzheimer
  • Comparative proteomics
  • Neuroblastoma
  • Transgenic
  • Two-dimensional gel electrophoresis

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