Short talk by Carsten Hopf
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, Paul-Wittsack Str. 10, 68163, Mannheim, Germany.
Faculty of Medicine, Heidelberg University, Grabengasse 1, 69117 Heidelberg, Germany
Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
Multimodal MALDI Lipid-Protein Imaging of Amyloid-β Plaques and Machine Learning reveal Alzheimer’s Disease Signatures
Alzheimer’s disease (AD), the leading cause of dementia, is characterized by deposition of amyloid-β peptides and various lipids in plaques. This study investigates the lipid and protein heterogeneity of amyloid-β (Aβ) plaques in the APP PS1 mouse model and in post-mortem brain samples from AD patients as well as in plaque-bearing but cognitively unimpaired individuals. We combined multimodal MALDI imaging of lipids and proteins at a single-plaque level on various mass spectrometry platforms with computational assessment of lipid and protein composition in large plaque populations. We identified distinct populations of amyloid plaques characterized by differential Aβ and lipid composition. These findings suggest that the heterogeneity in Aβ metabolism and lipid homeostasis is a key factor in the pathogenesis of AD and imply that total amyloid burden alone is an insufficient marker for the disease.
Brain sections of APP PS1 mice were analyzed by MALDI imaging on a neoflex benchtop MALDI-TOF mass spectrometer (Bruker). Lipid and HiPlex-MALDI-IHC information were obtained from the same tissue section. Multimodal MALDI lipid-protein imaging of fresh-frozen human brain sections was performed on a timsTOFflex mass spectrometer (Bruker). Computational evaluation of amyloid plaque-like objects was performed using the PlaquePicker R tool (Enzlein et al. 2020). Different machine learning approaches were utilized, in order to identify a mixed lipid-protein classifier characteristic for AD (Enzlein et al. 2024).
Amyloid beta plaques were segmented using PlaquePicker and differentiated based on their lipid and peptide composition. Combination of MALDI lipid imaging and HiPLEX-IHC demonstrated extensive co-localization of gangliosides as well as with microglia and activated astrocytes with Aβ plaques. However, we identified only one class of plaques in the APP PS1 mouse model. In contrast, multimodal MALDI lipid-protein imaging of human brain samples followed by statistical single-plaque analysis and machine learning, revealed marked differences between plaques in AD tissue and in brains from plaque-bearing but cognitively unimpaired (AP-CU) individuals. Surprisingly, three different machine learning models suggested that Aβ1-38 and distinct gangliosides rather than Aβ1-42 which is believed to drive amyloid plaque formation, most strongly distinguishes between AD- and APCU amyloid plaques. The combination of these molecular markers in multimodal MS imaging could be used to better understand AD pathology.