A novel transgenic rat model displaying the full Alzheimer-like amyloid pathology with early, preplaque-stage cognitive deficits

Background: Alzheimer's disease (AD) is a neurodegenerative disorder in which amyloid-beta (Aβ) accumulates in different areas of the brain, leading to the deposition of amyloid plaques and the progressive decline of cognitive functions. While many transgenic mouse models of AD exist, only few rat models have been reported, most of which have failed to develop mature amyloid plaques. Here we report the generation and characterization of a new transgenic rat line, coded McGill-R-Thy1-APP, with an early intracellular (Aβ) accumulation phase and later phase of amyloid plaque deposition. Methods: A transgenic rat line has been developed that expresses the human amyloid precursor protein (APP) carrying both the Swedish and Indiana mutations under the control of the murine Thy1 promoter. Amyloid pathology, cognitive deficits and levels of phosphorylation of synaptic plasticity-related ERK1/2 and CREB proteins were investigated by immunohistochemistry and Western blot analysis while learning and memory was assessed with the Morris Water Maze. Results: McGill-R-Thy1-APP transgenic rats display an early phase of abnormal (AD-like) intraneuronal Aβ (iAβ) accumulation widespread throughout the cerebral cortex and the hippocampal formation. In the neocortex, the iAβ accumulation is most notable in pyramidal neurons of lamina 5, but also ubiquitously present in all cortical layers. iAβ accumulation progressively increases with aging, leading to the formation of extracellular Aβ amyloid plaques by 6 to 13 months of age. Amyloid plaques are initially detected in the hippocampus and spread, with time, to the cerebral cortex. Cognitive deficits are apparent as early as 3 months of age and worsen with the intracellular and extracellular Aβ load. These transgenic rats also reveal a dysregulation of the ERK1/2 phosphorylation suggesting a compromise of cell signalling and synaptic plasticity mechanisms. Conclusions: Our results support the idea that AD-like iAβ accumulation- in absence of extracellular amyloid material deposition- is sufficient to interfere with higher CNS functions such as learning and memory. The characterization of this transgenic model is currently being completed, with particular attention being given to the effect of iAβ on the disruption of the cell signalling pathways involved in memory formation.