| Abstract No.: | B-C2116 |
| Country: | Canada |
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| Title: | HUMAN APP OVER-EXPRESSION IN A TRANSGENIC RAT MODEL LEADS TO INTRACELLULAR Aβ ACCUMULATION AND AMYLOID PLAQUE DEPOSITION. |
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| Authors/Affiliations: | 1 Wanda Leon*; 1 Fabio Canneva; 1 Vanessa Partridge; 2 Lina Alhonen; 1 A. Claudio Cuello;
1 McGill University, Montreal, QC, Canada; 2 University of Kuopio, Finland
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| Content: | Objective. Many mouse models have been generated and have stimulated enormous progress towards the elucidation of pathological mechanims of Alzheimer’s disease (AD), and towards the development of therapeutical compounds that may prevent or slow the progresion of AD. However, few rat models have been developed, most of which show only intracellular amyloid-beta (Aβ) accumulation without amyloid plaque deposition. Rat models are more advantageous for AD studies, as cognitive behavioural testing is more established and elaborate. We have developed a transgenic rat model which expresses not only early intracellular Aβ accumulation but also late extracellular plaques. The objective of the current study is to characterize the rat model using behavioural, immunohistochemical and biochemical approaches.
Materials and Methods. A transgenic rat line was developed that expresses the human amyloid precursor protein (APP) carrying both the Swedish and Indiana mutations, under the control of the Thy1 promoter. Amyloid pathology, cognitive deficits and levels of phosphorylation patterns of synaptic plasticity-related ERK1/2 and CREB proteins are currently being studied. To assess this, we are currently performing immunohistochemistry, Morris Water Maze and Western blot analysis.
Results. The selected transgenic rat line, coded McGill-R-Thy1-APP, displays, at early stages, an extended phase of abnormal (AD-like) intraneuronal accumulation of Aβ, which is widespread throughout different cortical areas and the hippocampal formation. In the neocortex, the intracellular Aβ is most notable in pyramidal neurons of lamina 5, but ubiquitously found in all layers from lamina 2 to 6. Intracellular Aβ accumulation progressively increases with aging, leading to the formation of extracellular Aβ amyloid plaques by 9 to 11 months of age. Amyloid plaque deposition starts in the hippocampus, spreading later to neo- and parietal cortex areas, entorhinal cortex and even thalamus. Our preliminary Western blot results reveal an upregulation of ERK1/2 phosphorylation, when compared to non-transgenic littermate rats, as previously found in our UKUR-25 and UKUR-28 transgenic rat models, which coincides with the phase of intracellular Aβ accumulation. Preliminary behavioural studies show a significant difference in 13 month old transgenic rats (post-plaque stage), compared to non-transgenic littermate rats, during the learning phase of the Morris Water Maze. Behavioural testing for pre-plaque cohorts has yet to be performed. The characterization of this transgenic model is ongoing, paying particular attention to the effect of intracellular Aβ and extracellular plaque deposition on learning and memory acquisition.
Conclusions
Immunohistochemistry results show that this rat model of AD displays early intraneuronal accumulation of Aβ progressing in an age-dependent manner, leading to eventual plaque formation. This corresponds to behavioural deficits at later stages of the pathology.
(ACC acknowledges support from the CIHR, grant MOP6717)
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