Massive CA1/2 Neuronal Loss with Intraneuronal and N-Terminal Truncated Aβ42 Accumulation in a Novel Alzheimer Transgenic Model
2004; Elsevier BV; Volume: 165; Issue: 4 Linguagem: Inglês
10.1016/s0002-9440(10)63388-3
ISSN1525-2191
AutoresCaty Casas, Nicolas Sergeant, Jean‐Michel Itier, Véronique Blanchard, Oliver Wirths, Nicolien Van Der Kolk, Valérie Vingtdeux, Evita van de Steeg, Gwénaëlle Ret, Thierry Canton, Hervé Drobecq, Allan Clark, Bruno Bonici, André Delacourte, Jesús Bénavidès, Christoph Schmitz, Günter Tremp, Thomas A. Bayer, Patrick Benoit, Laurent Pradier,
Tópico(s)Prion Diseases and Protein Misfolding
ResumoAlzheimer'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 ADrelated 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 -amyloid (A) precursor protein.A x-42 is the major form of A 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 A and thioflavine-S-positive intracellular material but not with extracellular A 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 A 42 in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.
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