Entorhinal cell-specific changes as an initial cause of Alzheimer's disease
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Evidence shows that Alzheimer’s disease (AD) begins with subtle and anatomically restricted pathological changes within the brain, ultimately leading to widespread neuronal loss and dementia. While high numbers of extracellular amyloid plaques have traditionally been assigned a leading role, and still represents an important hallmark of the disease, such pathology does not seem to fully account for the observed neuronal loss and dementia. A unique pattern of neurofibrillary tangle-pathology is also associated with AD, however, such neuronal inclusions appear to account for only a small part of the neuronal loss. An intriguing possibility is that accumulation of intracellular amyloid-β (Aβ) peptides drive the initial change(s) that cause formation of both amyloid plaques and neurofibrillary tangles, and, crucially, widespread neuronal loss. Early pathological changes associated with AD brought attention to involvement of circuits in the medial temporal lobe memory system. A pivotal component of this system is the entorhinal cortex, which mediates information between the hippocampal formation and the neocortex. The entorhinal cortex has convincingly been implicated in the onset of AD, and loss of entorhinal layer II-neurons occurs already at initial stages of the disease. Of entorhinal layer II-neurons, those expressing the protein Reelin give rise to projections to the hippocampal dentate gyrus and this projection suffers from severe synaptic loss in early disease-stages. Based on this anatomical specificity along with findings that intracellular Aβ (iAβ) accumulates in entorhinal neurons, the overarching goal of this thesis is to contribute to an improved understanding of the relevance of the entorhinal cortex and entorhinal iAβ-pathology in AD. In particular, the main objective of this thesis is to describe the initial distribution of iAβ in the entorhinal cortex in a rat model of AD, focusing on whether this is a general or a layer specific feature, whether there is evidence for a neuron type-specific vulnerability to accumulation of iAβ, and whether findings obtained in the rat model can be related to human subjects with pathologically confirmed AD-related changes. Most of the experimental work presented here involves the McGill-R-Thy1-APP transgenic rat model, one of few rat models of AD. The overall architecture and wiring of the entorhinal cortex is best understood in rats, making this model attractive for probing early pathological changes in the entorhinal cortex at a cellular level. In Paper 1, I reviewed the literature on neuron-specific markers in the entorhinal cortex and added also new data bearing to emerging questions. I show that for the entorhinal cortex several neuroanatomical markers are distributed similarly across species, revealing the same morphological types of neurons. Further, I discuss how unique populations of principal neurons, and interneurons targeting these, associate with specific neuronal markers and how this may relate to functional characteristics. In Paper 2, we characterize the onset and subsequent spread of extracellular amyloid pathology along with potential neuronal loss in the hippocampal region of the McGill- R-Thy1-APP transgenic rat model. We show that the model displays progressive accumulation of plaques with a spatial distribution similar to that observed in the initial stages of extracellular amyloid pathology in human AD-subjects. We also report that early on in the lifespan of these animals, expression of iAβ occurs among others in layer II of the entorhinal cortex. Meanwhile, neuronal loss does not appear to be a prominent feature of this model, with only a minor loss evident in the subiculum in older animals. In Paper 3, we focus on iAβ and a hypothesis that Reelin-immunoreactive neurons located in layer II of the entorhinal cortex are particularly vulnerable to accumulation of this peptide. We test this hypothesis using the McGill-R-Thy1-APP transgenic rat model in addition to tissue from human subjects with pathologically confirmed ADrelated changes, including Braak stages I, III and V. Data from both the rat model and the human tissue supports our hypothesis. Specifically, in the rat model we find that Reelin-immunoreactive neurons in layer II of the entorhinal cortex selectively stain positive for iAβ during the early, pre-plaque stage. This association between Reelin and iAβ is present also in humans with pathologically confirmed AD-related changes. Furthermore, in the rat model we show that the expression of iAβ is strongest in Reelin-immunoreactive neurons located towards the rhinal fissure, closely following the expression-levels of the Reelin-protein itself. Based on this along with confocal imaging data, we argue that Reelin and iAβ of the -42 form may become structurally associated.