Multimodal Chemical Imaging to probe Alzheimer’s Disease Pathology

Význam tématu

The global increase in Alzheimer's disease among elderly populations creates an urgent demand for analytical techniques that can reveal the molecular events underlying plaque formation and tau pathology.
Established methods often fall short in providing simultaneous spatial resolution and chemical specificity required to dissect plaque heterogeneity and disease progression.
Combining MALDI Imaging mass spectrometry with luminescent conjugated oligothiophenes (LCO) fluorescence addresses these gaps by enabling in situ localization and characterization of both lipid and peptide species associated with distinct amyloid morphotypes.

Cíle a přehled studie / článku

This study presents a multimodal chemical imaging workflow designed to probe amyloid plaque polymorphism in transgenic mouse models and human post mortem brain tissue.
Key objectives include mapping lipid signatures in diffuse versus cored plaques, identifying peptide distributions (notably Aβ1-40, Aβ1-42 and pyroglutamate variants), and comparing sporadic AD cases to cognitively unaffected amyloid-positive (CU-AP) individuals.

Použitá metodika a instrumentace

The experimental pipeline integrates several complementary techniques:

• Cryosectioning: 12 um brain sections mounted on indium tin oxide coated glass and membrane slides
• LCO staining and hyperspectral fluorescence imaging: q-FTAA and h-FTAA probes to differentiate compact fibrils and diffuse assemblies
• Laser microdissection: selection of spectrally annotated plaques for micro-extraction
• Immunoprecipitation and MALDI-TOF MS profiling: targeted extraction and MS analysis of Aβ species
• MALDI Imaging MS: matrix deposition, laser-based desorption/ionization and TOF detection for spatial ion distribution maps

Hlavní výsledky a diskuse

Hyperspectral LCO imaging combined with MALDI Imaging identified ceramides and short-chain gangliosides enriched in diffuse plaques, whereas ceramide-1-phosphate localized predominantly to cored, mature deposits, suggesting lipid remodeling during plaque maturation.
Peptide profiling revealed Aβ1-42 as the dominant species in diffuse deposits in both s-AD and CU-AP brains, while Aβ1-40 accumulation correlated specifically with cored plaque cores in AD tissue.
Notably, N-terminal pyroglutamate truncations (Aβ3pE-42 and Aβ11pE-42) were markedly elevated in AD plaques but absent in CU-AP diffuse deposits, implicating pyroglutamation in pathological plaque maturation.
These findings challenge prevailing views by highlighting Aβ4-42 as a major non-specific plaque component and refining the roles of Aβ1-42 and pyroglutamate variants in neurotoxic deposit formation.

Přínosy a praktické využití metody

The multimodal approach delivers orthogonal biochemical information directly on tissue sections, enabling high-resolution mapping of disease-relevant molecules.
This strategy facilitates the discovery of lipid and peptide biomarkers, improves understanding of plaque heterogeneity, and can guide therapeutic targeting and diagnostic development in neurodegenerative research.

Budoucí trendy a možnosti využití

Future directions include extending this workflow to other proteinopathies and neurodegenerative conditions, integrating spatial transcriptomics or proteomics for deeper molecular context, and applying high-performance MALDI platforms to achieve subcellular resolution.
Adapting these imaging modalities for clinical biopsy analysis may accelerate translational research and personalized medicine approaches in Alzheimer's disease.

Závěr

Multimodal chemical imaging combining MALDI mass spectrometry with LCO hyperspectral fluorescence offers a powerful platform to dissect amyloid plaque polymorphism and associated biochemical changes.
The approach yields novel insights into lipid remodeling and peptide modifications that underlie plaque maturation, challenging established paradigms and revealing potential biomarkers for early diagnosis and therapeutic intervention.

Reference

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