Revealing Mechanisms of Sporadic Alzheimer’s Disease by Modelling in Organotypic Hippocampal Slice Cultures


Type
Thesis
Change log
Authors
Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative condition which affects millions of people throughout the world. It is the most common form of dementia and manifests with progressive memory impairment and cognitive decline. While a small proportion of AD cases are inherited, a majority of patients have sporadic disease. Thus, it is a combination of one’s genes, environment and lifestyle which ultimately determine whether they develop dementia. Two of the defining hallmarks of AD include deposits of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tau tangles. These coincide with reduced hippocampal and cortical volume, synapse loss, and signs of inflammation. Neuropathology and some known genetic and environmental risk factors help give clues as to the pathogenesis of AD, but we still lack a fundamental knowledge of how exactly this disease comes to fruition. Many environmental risk factors have now been associated with an increased risk of developing AD. Amongst others, these include activators of inflammation, cardiovascular disease, sedentary life style, pollution, smoking, diabetes, and stress. Inflammation which can occur due to infection and/or trauma is closely related to AD risk, and a common denominator between many of the other environmental risk factors. Vascular impairment, resulting in illnesses such as stroke and heart disease, is also closely linked to dementia, and in fact shares many risk factors with AD. Organotypic hippocampal slice cultures (OHSCs) are an underused tool in dementia research. They contain a variety of cell types including neurons, astrocytes, microglia, and oligodendrocytes, and maintain some of the structure and connections of the hippocampus. Yet, slice cultures are an in vitro system, and thus are easy to work with, without the constraints of the blood brain barrier. The major aim of this work was to use OHSCs as a means of studying sporadic AD. This was performed by carrying out experiments where environmental risk factors and sporadic genetic risk factors were modelled in the slice culture system. While multiple individual risk factors resulted in alterations in either Aβ, tau or synaptic proteins, there are several key findings within this thesis. First, modelling inflammation in wild type OHSCs results in a microglia-dependent decrease in the presynaptic protein synaptophysin. Next, lowering glucose concentration to model hypoglycaemia, causes an increase in Aβ in wild type OHSCs, which can be rescued with a variety of alternative fuel sources. And finally, OHSCs cultured from a mouse transgenic line show that the presence of the human APOE4 allele results in a decrease in synaptophysin levels relative to cultures with humanised APOE3. These results show how environmental and genetic risk factors can directly result in AD biomarker pathology in an in vitro system, without the need for the presence of a dominantly inherited causal mutation of AD, and they provide a basis for testing combinatorial risks to model disease in more sporadic cases.

Description
Date
2022-05-01
Advisors
Coleman, Michael
Keywords
Alzheimer's disease, sporadic disease, inflammation, glucose, amyloid beta, synaptophysin
Qualification
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Sponsorship
Alzheimer's Research UK project grant