Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model

Caty Casas, Nicolas Sergeant, Jean-Michel Itier, Véronique Blanchard, Oliver Wirths, Nicolien van der Kolk, Valérie Vingtdeux, Evita van de Steeg, Gwenaëlle Ret, Thierry Canton, Hervé Drobecq, Allan Clark, Bruno Bonici, André Delacourte, Jesús Benavides, Christoph Schmitz, Günter Tremp, Thomas A Bayer, Patrick Benoit, Laurent Pradier

Research output: Contribution to journalArticle

337 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.
Original languageEnglish
Pages (from-to)1289-300
Number of pages12
JournalAmerican Journal of Pathology
Volume165
Issue number4
Publication statusPublished - Oct 2004

Keywords

  • Age Factors
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Electrophoresis, Gel, Two-Dimensional
  • Female
  • Gene Dosage
  • Gliosis
  • Hippocampus
  • Humans
  • Immunoassay
  • Immunohistochemistry
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Degeneration
  • Peptide Fragments
  • Presenilin-1
  • Pyramidal Cells

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