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, 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
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health Faculty of Medicine and Health Sciences > Research Groups > Health Services and Primary Care Faculty of Medicine and Health Sciences > Research Groups > Norwich Clinical Trials Unit Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023) Faculty of Medicine and Health Sciences > Research Centres > Population Health
Depositing User:	Pure Connector
Date Deposited:	20 Jan 2014 15:56
Last Modified:	06 Feb 2025 04:42
URI:	https://ueaeprints.uea.ac.uk/id/eprint/46112
DOI:	10.1016/S0002-9440(10)63388-3

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