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

Casas, Caty, Sergeant, Nicolas, Itier, Jean-Michel, Blanchard, Véronique, Wirths, Oliver, van der Kolk, Nicolien, Vingtdeux, Valérie, van de Steeg, Evita, Ret, Gwenaëlle, Canton, Thierry, Drobecq, Hervé, Clark, Allan ORCID: https://orcid.org/0000-0003-2965-8941, Bonici, Bruno, Delacourte, André, Benavides, Jesús, Schmitz, Christoph, Tremp, Günter, Bayer, Thomas A, Benoit, Patrick and Pradier, Laurent (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. American Journal of Pathology, 165 (4). pp. 1289-300. ISSN 0002-9440

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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.

Item Type: Article
Uncontrolled 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,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 20 Jan 2014 15:56
Last Modified: 28 Sep 2022 00:19
URI: https://ueaeprints.uea.ac.uk/id/eprint/46112
DOI:

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