Structural and functional changes in the hippocampal region of a transgenic rat model of Alzheimer's disease
MetadataShow full item record
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently has no treatment to halt or cure the disease. Among the first symptoms are memory loss and learning difficulties, and as the disease progresses, more and more cognitive functions are affected. The hippocampal region is essential for formation and recall of memories, and is affected early in Alzheimer’s disease. Understanding more about the early processes leading to the cognitive dysfunctions could help to diagnose the disease and develop treatments. Animal models have been of great use to understand the normal function of the brain and are also valuable tools for understanding the pathological processes in disease. The main goal of this thesis was to characterize pathological changes in the hippocampal region of the McGill-R-Thy1-APP transgenic rat, one of the few rat models of Alzheimer’s disease. The three main pathological hallmarks of Alzheimer’s disease are amyloid plaques, neurofibrillary tangles and neuronal death. In Paper I in this thesis, the onset and spread of plaque pathology and possible neuron loss in the hippocampal region was assessed. The results show that the McGill-R-Thy1-APP rat has a progressive accumulation of plaques that mimics the early phases in human Alzheimer’s patients, while the neuron loss is more limited than in patients. Paper II and III looked at possible changes in the physiology of networks and single cells in the hippocampal region in the transgenic AD rats. The main finding from Paper II was that the networks were not hyperexcitable, and there were only subtle changes in the patterns of activity. Paper III demonstrates that the electrophysiological properties and excitability of single neurons in the entorhinal cortex are also largely unaltered, although these cells expressed high levels of intracellular amyloid β. The findings in this thesis contribute to the understanding of the pathological processes of Alzheimer’s disease in the neural networks crucial for memory. The results also highlight that specific parts of the hippocampal region are more vulnerable to amyloid β pathology. They also support the concept of a spread of pathology through anatomically connected areas. Furthermore, these findings point to avenues of research that could further contribute to the understanding of the dysfunction underlying the early cognitive deficits seen in Alzheimer’s disease.