Unveiling the Structural Proteome of an Alzheimer’s Disease Rat Brain Model

Abstract

Studying native protein structures at near-atomic resolution in crowded environment presents a challenge. Consequently, understanding the structural intricacies of proteins within pathologically affected tissues often relies on mass spectrometry and proteomic analysis. In this study, we utilized electron cryomicroscopy (cryo-EM) and a specific method of analysis called Build and Retrieve (BaR) to investigate structural characteristics of protein complexes such as post-translational modification, active site occupancy, and arrested conformational state in Alzheimer’s Disease (AD) using brain lysate from a rat model (TgF344-AD) of the disease. Our findings reveal novel insights into the architecture of these complexes, which we corroborate through mass spectrometry analysis. Interestingly, it has been shown that the dysfunction of these protein complexes extends beyond AD, implicating them in cancer, as well as other neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, and Schizophrenia. By elucidating the structural details of these complexes, our work not only enhances our understanding of disease pathology but also suggests new avenues for future approaches in therapeutic intervention.