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Entorhinal cell-specific changes as an initial cause of Alzheimer's disease

Kobro-Flatmoen, Asgeir
Doctoral thesis
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URI
http://hdl.handle.net/11250/2441140
Date
2017
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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.
Publisher
NTNU
Series
Doctoral theses at NTNU;2017:74

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