Dataset Information

Integrative single-plaque analysis reveals signature Aβ and lipid profiles in the Alzheimer’s brain

ABSTRACT: Utilizing multimodal mass spectrometry imaging (MSI) combined with machine learning techniques, this study investigates the molecular heterogeneity of amyloid-β (Aβ) plaques and associated lipid profiles in post-mortem brain samples from Alzheimer’s disease (AD) and amyloid-positive cognitively unaffected (AP-CU) individuals. Our analytical approach permitted single-plaque level investigation, revealing distinct populations of amyloid plaques characterized by differential Aβ and lipid compositions. Notably, the integration of MSI data with machine learning based feature extraction enabled the identification of Aβ38 and ganglioside GM1 as significant molecular markers differentiating AD from AP-CU pathology. These findings suggest that the heterogeneity in Aβ metabolism and lipid homeostasis, as revealed through precise analysis, is a key factor in the pathogenesis of AD and implies that total amyloid burden alone is an insufficient marker for the disease. The application of MSI and machine learning based feature extraction in this context exemplifies a progressive analytic strategy to unravel complex biochemical phenomena, offering potential pathways for the refinement of diagnostic tools and deepening the understanding of neurodegenerative diseases from an analytical chemistry perspective.

INSTRUMENT(S): rapifleX, timsTOF fleX

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Thomas Enzlein

LAB HEAD: Carsten Hopf

PROVIDER: PXD049325 | Pride | 2024-06-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	AP-CU_pride.txt	Txt
	S15_210716_pa_ucl_pa_neg.ibd	Other
	S15_210716_pa_ucl_pa_neg.imzML	Other
	S15_210716_pa_ucl_s15_pa_pep.ibd	Other
	S15_210716_pa_ucl_s15_pa_pep.imzML	Other

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Project description:Aberrant protease activity has been implicated in the etiology of various prevalent diseases including neurodegeneration and cancer, in particular metastasis. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has recently been established as a key technology for bioanalysis of multiple biomolecular classes such as proteins, lipids, and glycans. However, it has not yet been systematically explored for investigation of a tissue’s endogenous protease activity. In this study, we demonstrate that different tissues, spray-coated with substance P as a tracer, digest this peptide with different time-course profiles. Furthermore, we reveal that distinct cleavage products originating from substance P are generated transiently and that proteolysis can be attenuated by protease inhibitors in a concentration-dependent manner. To show the translational potential of the method, we analyzed protease activity of gastric carcinoma in mice. Our MSI and quantitative proteomics results reveal differential distribution of protease activity – with strongest activity being observed in mouse tumor tissue, suggesting the general applicability of the workflow in animal pharmacology and clinical studies.Aberrant protease activity has been implicated in the etiology of various prevalent diseases including neurodegeneration and cancer, in particular metastasis. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has recently been established as a key technology for bioanalysis of multiple biomolecular classes such as proteins, lipids, and glycans. However, it has not yet been systematically explored for investigation of a tissue’s endogenous protease activity. In this study, we demonstrate that different tissues, spray-coated with substance P as a tracer, digest this peptide with different time-course profiles. Furthermore, we reveal that distinct cleavage products originating from substance P are generated transiently and that proteolysis can be attenuated by protease inhibitors in a concentration-dependent manner. To show the translational potential of the method, we analyzed protease activity of gastric carcinoma in mice. Our MSI and quantitative proteomics results reveal differential distribution of protease activity – with strongest activity being observed in mouse tumor tissue, suggesting the general applicability of the workflow in animal pharmacology and clinical studies.

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Integrative single-plaque analysis reveals signature Aβ and lipid profiles in the Alzheimer’s brain

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