Correlative Chemical Imaging of Amyloid Plaque Pathology in Alzheimer’s Disease

Abstract

The formation of beta-amyloid (Aβ) plaques and neurofibrillary tangles are key pathological hall-marks of Alzheimer’s disease (AD), where amyloid has been identified to precede and even initiate other neurodegenerative processes including Tau. Consequently, studying beta-amyloid pathology has been a central focus in AD research yet the molecular mechanisms underlying plaque formation and its role in initiating AD remain poorly understood. Aβ plaque pathology is characterized by significant heterogeneity in morphology, including variations between cored and diffuse plaques, as well as structural polymorphism in amyloid fibril formation. Moreover, Aβ does not correlate with cognitive performance and is even observed in elderly, cognitively normal individuals. Recent evi-dence further suggests that neuronal lipids also play a crucial role in amyloid plaque formation and progressing plaque pathology. Together this poses a significant challenge and highlights the need for new, biochemical tools that allow to disentangle the complex molecular interactions associated with AD pathogenesis and plaque formation in particular. To address this gap, we utilized advanced chemical imaging techniques to probe the molecular events associated with diverse plaque pathologies in AD. In this thesis, we developed a tetra-modal chemical imaging approach that integrates matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) with fluorescence imaging. This allowed for detailed mapping of lipid and amyloid peptide distributions in brain tissue of ge-netic AD mouse models. Through the application of novel, multivariate tools for multiblock analy-sis, we identified distinct lipid profiles linked to different stages of plaque formation, highlighting the correlation of GM1 ganglioside with both plaque seeding and growth. We further validated the relevance of lipid-amyloid co-aggregation by developing a dynamic imaging approach based on metabolic labeling of lipids and peptides with stable isotopes. This allowed to dissect plaque and lipid coaggregation dynamics and identified the sequence of ganglioside and amyloid deposition in precipitation plaque pathology in AD mouse model. Furthermore, we examined the co-existence of different Aβ peptides in novel transgenic models harboring the Uppsala APP mutation, revealing its significant impact on Aβ aggregation dynamics. Finally, we applied these advanced imaging techniques to understand heterogenous plaque pathol-ogy in the human brain. Here, we successfully identified specific amyloid plaque signatures for distinct plaque types, such as Aβ1-42(ox) and Aβ2-42 in neuritic plaques. Using a novel AI driven plaque segmentation scheme, we identified that Aβ1-40 was found to be associated with plaque maturation into cored deposits in AD patients. Further, Aβ x-40 is present in cored, coarse grain plaques and vascular plaques (CAA) in both sAD and fAD. Together these findings enhance our understanding of amyloid plaque heterogeneity as well as un-derscore the importance of lipid-amyloid interactions in AD pathology. This work lays the ground-work for future investigations aimed at elucidating the complex interactions between lipids and am-yloid peptides in the context of AD.