Lipid mediated formation of antiparallel aggregates in cerebral amyloid angiopathy

Area of Science:

• Neuroscience
• Biochemistry
• Medical Imaging

Background:

• Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by amyloid-β (Aβ) deposition in brain blood vessels, often leading to hemorrhage and stroke.
• While sharing amyloid-β pathology with Alzheimer's disease (AD), the precise structural forms and chemical associations of Aβ in CAA remain unclear.
• Existing methods may miss the heterogeneity and polymorphic nature of vascular amyloid aggregates.

Purpose of the Study:

• To investigate the chemical structure and heterogeneity of vascular amyloid aggregates in human brain tissues across different stages of CAA.
• To elucidate the structural variations of amyloid-β (Aβ) deposits and their relationship with disease progression and co-localized molecules.

Main Methods:

• Utilized sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to analyze vascular amyloid aggregates directly in human brain tissue.
• Employed nanoscale AFM-IR spectroscopy to validate ex-vivo findings and study in-vitro Aβ aggregation with lipids.
• Examined amyloid-β (Aβ) structural distributions in relation to disease severity and lipid co-localization.

Main Results:

• Demonstrated a progressive increase in β-sheet content within vascular Aβ deposits correlating with CAA severity.
• Identified a significant abundance of antiparallel β-sheet structures, particularly in moderate to severe CAA cases.
• Observed a strong correlation between antiparallel Aβ structures and co-localized lipids, suggesting a lipid-mediated aggregation mechanism.

Conclusions:

• The study reveals distinct structural polymorphs of amyloid-β (Aβ) in cerebral amyloid angiopathy (CAA), including antiparallel β-sheets, which increase with disease severity.
• Lipid co-localization with antiparallel Aβ structures suggests a lipid-driven aggregation pathway in CAA.
• These findings offer critical insights into Aβ aggregate structures in CAA, potentially explaining alternate neurotoxic mechanisms beyond traditional fibril models.