Early Isoform-dependent Effects of Human Apolipoprotein E on Alzheimer’s disease Pathobiology
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.