Sammendrag
Alzheimer’s disease is a progressive neurodegenerative disorder which is the most common cause of dementia. Pathologically it is characterized by senile plaques consisting of amyloid beta (A-beta), neurofibrillary tangles and neuronal death. Areas affected early in the disease include the hippocampal formation and parahippocampal region, with reports of loss of up to 90% of the neurons in layer II of the entorhinal cortex. These structures are strongly implicated in episodic memory and have been shown to be important for spatial memory and navigation in rodents. The McGill-R-Thy1-APP rat is one of the few transgenic rat models of Alzheimer’s disease. This rat expresses human APP carrying the Swedish double and Indiana mutations under control of the murine Thy1.2 promoter. Deficits in spatial memory have been reported by three months of age and becomes more prominent in older animals. Intraneuronal A-beta accumulation can be seen as early as 1 week after birth and extracellular plaques can be found in the subiculum and entorhinal cortex by six months. In older rats the plaque pathology spreads to the other areas of the hippocampus, then to the cerebral cortex and eventually to most parts of the brain.
We further characterized the McGill-R-Thy1-APP transgenic rat by investigating possible neuron loss in the hippocampal and parahippocampal regions. A pilot study estimating the neuronal number in 6 and 9 month old animals showed no significant neuronal loss in any of the areas (CA1, CA2, CA3, dentate gyrus, subiculum, presubiculum, parasubiculum, medial entorhinal cortex (MEC), lateral entorhinal cortex (LEC), postrhinal and perirhinal cortex). However, there was a trend towards lower neuron numbers in LEC. Based on these results and the known plaque pathology, the subiculum, MEC, and LEC were chosen for further study in older rats. Brains from 18 month old homozygous transgenic and control rats were cut coronally in 50 µm thick sections and stained with Cresyl violet. Stereological estimates of the total neuron number in these areas were obtained using the optical fractionator. There were no significant differences in the neuron numbers in the transgenic rats compared to the controls, but there was a trend of neuron loss in the subiculum and the variability in the estimates was higher in the transgenic group than the control group. In addition, work is in progress to quantify the plaque load over time in these areas, and these results will be correlated to the neuronal numbers. Overall, no overt cell loss was observed in the McGill-R-Thy1-APP rat model at 18 months.
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