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From the Departments of Central Nervous System/Alzheimer Disease* and Functional Genomics, Aventis-Pharma Paris Research Center, Vitry sur Seine, France; INSERM U422, Groupe Vieillissement Cérébral et Degenerescence Neuronale, Equipe Proteomique, Lille, France; UMR8525,|| Centre National de la Recherche Scientifique, Institut de Biologie de Lille, Université de Lille II, Lille, France; the Department of Psychiatry, Division of Neurobiology, Saarland University, Homburg/Saar, Germany; and the Department of Psychiatry and Neuropsychology,¶ Division of Cellular Neuroscience, Maastricht University, Maastricht, The Netherlands
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 ß-amyloid (Aß) precursor protein. Aßx-42 is the major form of Aß 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 Aß and thioflavine-S-positive intracellular material but not with extracellular Aß 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 Aß42 in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.
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