| dc.description.abstract | 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. | nb_NO |
