How a Rare APOE Variant Protects Against Alzheimer’s Disease
MentorGuojun Bu, PhD
The goal of this project is to understand how APOE3-Christchurch confers its protective effect against Alzheimer's disease onset, to inform therapy. Aim 1 is to examine the effects of apoE3-Ch on AD-related pathology and toxicity in amyloid model mice. We will look at the effects of astrocytic, hepatic, and systemic apoE3-Ch in early and late amyloid stages. Aim 2 is to define the functional consequences associated with altered biochemical properties of apoE3-Ch/lipoprotein particles. The biochemical and biophysical properties of non-lipidated and native, glia-secreted apoE3-Ch will be characterized. Then, their effects on neuronal homeostasis and AD-related pathologies will be assessed in iPSC-derived neurons and organoids.
The greatest innovation pertains to the scope of this study. In addition to revealing any possible impact of apoE3-Ch on amyloid pathology for the first time, we aim to offer an extremely thorough characterization of, and comparison between, the biochemical function of apoE isoforms/lipoprotein particles. The identification of any differences between apoE3-Ch and apoE3 will deepen our understanding of which functional aspect of apoE is protective and which is detrimental; while any differences between apoE3-Ch and apoE2 may point to different possible protective pathways against Alzheimer's. With APOE being the main genetic modulator of sporadic Alzheimer's disease onset, there is a great interest in the field in furthering our understanding of how apoE impacts disease progression. Grasping the full extent at which a genetic factor, such as APOE3-Ch, may be protective is as equally important as understanding how a factor may present a risk, as new therapeutic strategies could arise. The rise of apoE-targeted therapies would provide new avenues on how to prevent and/or treat Alzheimer’s disease.