Temporal, Spatial and Cellular Dynamics of Amyloid Plaque Deposition

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Project Summary Amyloid plaques are one of the canonical pathological hallmarks of Alzheimer's disease (AD). The amyloid hypothesis is a standard model for amyloid Abeta pathogenesis that has driven drug discovery for the past 25 years, giving rise to many clinical failures, including drugs that make the treated patients cognitively worse than the placebo-treated controls. Aducanumab (Aduhelm) is the first disease modifying treatment recently approved by the FDA on the basis of its ability to facilitate the removal of amyloid plaques, indicating the importance of these strictures. There are several different types of plaques and amyloid deposits known in AD, including diffuse, “classical” “dense core”, neuritic plaques and cerebrovascular amyloid (CVA) and intraneuronal amyloid deposits. While there is much that is known about amyloid plaque morphology and composition in AD, less is known about mechanisms of plaque deposition, their dynamics and interrelationships, the contributions of different cell types to their formation and their significance for AD pathogenesis. We seek to investigate these critical aspects of amyloid plaque deposition in a detailed and un unbiased fashion by labeling the proteome of specific cell types with the non-canonical amino acid, azidonorleucine, and following the incorporation of ANL-labeled proteins into amyloid deposits. The goal of this proposal is to determine the temporal, spatial and cellular dynamics of amyloid deposition using cutting-edge biorthogonal non-canonical amino acid tagging (BONCAT) technology and specific Cre driver mouse lines for cell specific synthesis of clickable proteins, exploiting click chemistry for fluorescence localization (FUNCAT), purification and enrichment and biochemical analysis. Our central hypothesis is that different types of plaques are deposited by different mechanisms at different times and locations by different populations neurons and that some of these types of plaques may be mechanistically unrelated to the other types of amyloid and may be differentially associated with pathogenesis and neuronal degeneration.