Biochemistry and Structural Modeling Core

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PROJECT SUMMARY (APOE U19 Core B: Biochemistry and Structural Modeling Core) The APOE gene, which encodes the apoE protein, is the strongest genetic risk factor for Alzheimer’s disease (AD). However, it remains unclear how different apoE isoforms impact aging and AD. The overall goal of this U19 proposal is to test the ApoE Cascade Hypothesis (ACH) that the biochemical and structural differences between apoE isoforms initiate their differential effects on a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. One hurdle to testing this hypothesis is that the field currently lacks a detailed understanding of the biochemical and structural properties of different apoE isoforms in their native, lipid-bound states—called lipoproteins. Core B will provide biochemistry and structural modeling services to support other U19 projects/cores, helping to uncover the biochemical composition and atomically-detailed structures of lipoproteins. Specifically, we will establish standard protocols for isolating lipoproteins and characterizing their size distribution, lipid composition, and post-translational modifications. We will also develop methods for integrating information from molecular dynamics simulations and structural experiments performed in Project 1 to build atomically-detailed models of the ensemble of structures that lipoproteins adopt. The Core will analyze the data generated to identify signatures that are predictive of the impact of different apoE isoforms on aging and AD.