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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Rylett, Jane

Abstract

The ε4 allele of apolipoprotein E (ApoE4) is the strongest risk factor for sporadic Alzheimer’s disease (AD), increasing the risk of developing the disease by up to twelve-fold. However, the mechanisms by which ApoE4 promotes AD pathogenesis, particularly in presymptomatic stages of the disease, are poorly understood. AD is the most common cause of dementia in older individuals and is becoming more prevalent globally. Prevailing evidence suggests that AD etiology is due to complex interactions among various cell types in the brain, leading to early molecular alterations that impair a wide range of cellular processes. In this thesis, I utilized a genetically modified mouse model expressing either human ApoE3 or ApoE4 to examine how ApoE4 modulates various molecular pathways altered in AD. I fed ApoE3- and ApoE4-expressing mice a high-fat diet (HFD) and evaluated their combined effects on various AD-related metabolic and genetic outcomes. My investigations revealed the presence of early molecular alterations in HFD-fed ApoE4 mice, including changes in body weight, peripheral blood glucose, plasma insulin level, and expression of genes involved in the insulin resistance, synaptic plasticity, and AD pathogenesis. To my knowledge, these findings represent the earliest age at which AD-related molecular alterations related to the interplay between ApoE genotype and diet have been reported. Second, using the same animal model, I investigated the effects of ApoE4 genotype on steady-state protein levels of glial fibrillary acidic protein (GFAP), an AD biomarker and astrocyte cytoskeletal protein detectable in plasma during the early stages of AD pathobiology. I found that ApoE4-positivity markedly reduced GFAP protein levels in 8-month-old mice, compared to ApoE3. My studies also revealed that GFAP interacts stably with two Rab proteins – Rab5A and Rab7 – both of which are involved in the trafficking of endosomes within astrocytes. Loss of GFAP led to impaired localization of neurotoxic amyloid-β (Aβ) peptides to lysosomes and altered the size of Rab5A- and Rab7-positive endosomes within astrocytes. Taken together, my findings highlight early molecular changes caused by ApoE4 genotype which may have implications for the risk and progression of AD.

Summary for Lay Audience

The ε4 allele of apolipoprotein E (ApoE4), a protein involved in the transport of cholesterol and other lipids throughout the brain, is the strongest risk factor for developing Alzheimer’s disease (AD). However, how ApoE4 increases the brain’s vulnerability to AD risk, particularly in early age before the emergence of clinical symptoms of the disease, is largely unknown. AD is the leading cause of dementia in older individuals and is becoming more prevalent globally. It is widely accepted that AD is caused by complex interactions among multiple cell types in the brain, leading to changes in various molecular pathways. In my research, I used mice that had been modified to express either human ApoE4 or a more common variant called ApoE3. These mice were fed a high-fat diet (HFD) and I looked at how this affected a wide range of molecular processes related to AD. I found that HFD-fed ApoE4 mice showed early AD-like molecular alterations; these changes included differences in weight gain, blood sugar levels, insulin levels, and the activity of certain genes linked to AD. Next, using the same mouse model, I looked at the effects of ApoE4 on a protein called glial fibrillary acidic protein (GFAP), which is found in brain cells called astrocytes, and is detectable in the plasma during the early stages of AD. I found that mice carrying the ApoE4 gene had lower levels of GFAP when compared to mice with the ApoE3 gene. Furthermore, I discovered that GFAP interacts with two other proteins, Rab5A and Rab7, which are enzymes involved in transporting neurotoxic proteins called amyloid-β (Aβ) within brain cells. When GFAP levels were reduced, the transport of these neurotoxic proteins to astrocyte cell compartments where they can be degraded was altered, which could contribute to AD progression. Overall, my research sheds light on how the ApoE4 gene influences early molecular changes that may affect the risk and development of AD.

Creative Commons License

Creative Commons Attribution-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.

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