A Multi-Faceted Quantification of Myelin Dysregulation in AD and Links to Amyloid and Tau - PROJECT SUMMARY/ABSTRACT Myelin is the insulating sheath around neuronal axons (consisting of 25% proteins/75% lipids) that facilitates fast and efficient signal transduction. In the recent years, its plasticity has been shown to be key for cognition, memory formation and consolidation. Alzheimer’s disease (AD) debilitates cognition and memory, with amyloid and tau being hallmarks of the disease, yet its onset and progression mechanisms remain unresolved. Recent evidence from imaging, proteomics, and genomics support myelin’s involvement in AD, as well as interactions with amyloid, tau, and neuroinflammation. Yet myelin’s role, pattern of degeneration, and interplay with AD pa- thology remain unknown. A limiting factor has been the lack of myelin studies integrating different scales: a ma- croscopic myelin imaging method with targeted molecular profiling and correlations with known AD pathologies. We aim to address this important knowledge gap by combining three innovative approaches. First, our novel synchrotron X-ray imaging (SAXS-TT) that is specific to myelin due to photons diffracting off the periodic myelin sheath and provides quantitative 3D maps of myelin levels and integrity. Second, molecular profiling of AD tissue using spatial (lipid/transcript)-omics and exosomes, nanosized vesicles whose cargo reflects active cellular processes, to identify molecular biomarkers of myelin degeneration. Third, translating quantitative mye- lin mapping in vivo and combining with Αβ and tau molecular imaging to test their interactions in living subjects. The project aims are: (1) To map AD-specific myelin degeneration and biochemical dysregulation. We will SAXS-TT-scan low AD, high AD, PD/LBD, and normal aging hippocampal specimens (10/group), segment subfields/tracts (also using our novel SLI method), and test vulnerable regions for AD-specific myelin degener- ation. Performing spatial -omics, we will map and identify biochemical correlates of myelin degeneration. (2) To identify biological processes linking myelin changes to hallmark AD pathologies. We will section Aim 1 specimens, stain for Αβ, tau, and microglia and register histology with imaging using our novel micron-scale- precision serial blockface pipeline. Spatially correlating myelin levels and integrity with Αβ/tau/microglia stains will test two literature-supported hypotheses: that myelin degeneration overwhelms microglia inhibiting Αβ clearance, or that tau propagates via demyelinating tracts. (3) To translate quantitative myelin mapping and link to Aβ & tau molecular imaging. We will validate MR myelin- sensitive sequences using SAXS-TT to identify the most myelin-specific one. This will be translated to a clinical scanner using latest methods for fast and high-resolution elderly patient scanning, and applied on 24 subjects (control, MCI, AD, PD-LBD, 6/group), who will also be Aβ- and tau-PET-scanned. Myelin quantification will be correlated to Aβ/tau maps and cognitive scores, testing interaction hypotheses at whole-brain level in vivo. This study will combine macroscopic with molecular analyses to provide a multi-faceted view of myelin’s role in AD.
