Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ<inf>42</inf> 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 journalArticleResearchpeer-review

    332 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, APPSLPS1KI 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 β-amyloid (Aβ) precursor protein. Aβx-42 is the major form of Aβ species present in this model with progressive development of a complex pattern of N-truncated variants and dinners, 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 Aβ and thioflavine-S-positive intracellular material but not with extracellular Aβ 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, APPSLPS1KI mice further confirm the critical role of intraneuronal Aβ42 in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.
    Original languageEnglish
    Pages (from-to)1289-1300
    JournalAmerican Journal of Pathology
    Volume165
    Issue number4
    DOIs
    Publication statusPublished - 1 Jan 2004

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