Connecting Apolipoprotein E and the Mevalonate Pathway: Insights on the Lipid Biology of Alzheimer's Disease

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by cognitive decline and pathological accumulation of amyloid-β plaques and neurofibrillary tau tangles. The strongest genetic risk factor for development of late-onset AD is the ε4 allele of Apolipoprotein E (ApoE), which is one of three ApoE alleles found in humans next to the ε2 and ε3 alleles. ApoE is an integral component of HDL-like lipoparticles that are made and secreted predominantly by astrocytes in the adult brain in order to shuttle cholesterol, lipids, and proteins to other cells. Previously, our lab has shown that development of both amyloid and tau pathology in a mouse model of AD requires astrocyte cholesterol synthesis through the mevalonate pathway, yet whether this pathway modulates ApoE is not well-known.

The mevalonate pathway is responsible for controlling two vital cellular processes, cholesterol production and generation of substrates to be used for protein prenylation. Prenylation is a post-translational modification where an isoprenyl group is added to a protein in order to make it more lipophilic. This is particularly important for some proteins, such as the Ras superfamily of small GTPases, which require prenylation to be embedded into membranes to subsequently signal and traffic cargo throughout the cell. Chapter 1 focuses on reviewing AD, ApoE, and the different arms of the mevalonate pathway, as well as how these interact with one another. In the experiments presented in Chapter 2, we show that extracellular ApoE levels from astrocyte cultures expressing each of the three human ApoE isoforms are regulated by a form of prenylation called geranylgeranylation, and that this effect is independent of ApoE isoform. We then find that short-term inhibition of prenylation in astrocytes specifically impairs the secretion of ApoE, not its reuptake into the cell.

In Chapter 3, additional experiments and preliminary data are presented as future directions to further characterize the interactions of the mevalonate pathway and ApoE. Given the increasing interest in targeting of ApoE for treating AD, it is imperative to understand the basic biology underlying the regulation of ApoE in order to more effectively modulate this protein therapeutically, and to identify novel targets for AD intervention. Altogether, the focus of this dissertation was to better characterize the interaction between the different arms of the mevalonate pathway and ApoE in order to gain insight into potential mechanisms underlying lipid biology and AD.