Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils.

Area of Science:

• Neuroscience
• Biophysics
• Biochemistry

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) peptide deposits in neuritic plaques and cerebral amyloid angiopathy (CAA).
• Aβ fibrils exhibit polymorphism, adopting different structures based on formation conditions.
• The structural variations between Aβ fibrils in plaques and blood vessels remain largely unexplored.

Purpose of the Study:

• To investigate whether Aβ fibrils from brain parenchyma differ structurally from those in cerebral blood vessels.
• To determine if distinct nucleation environments influence Aβ fibril conformation.

Main Methods:

• Amyloid-enriched material from brain parenchyma and cerebral blood vessels was used as seeds.
• Replicate Aβ fibrils were generated using seeding techniques.
• Solid-state NMR and X-ray diffraction were employed to analyze fibril structures.

Main Results:

• Solid-state NMR revealed chemical shift differences in specific Aβ residues (Ala2, Phe4, Val12, Gln15) between parenchymal and vascular-seeded fibrils.
• X-ray diffraction indicated greater order in the side-chain dimension of vascular-seeded fibrils compared to parenchymal-seeded fibrils.
• Both types of fibrils showed similar order in the hydrogen-bond dimension.

Conclusions:

• Nucleation conditions in different brain regions (parenchyma vs. blood vessels) influence the resulting Aβ fibril structures.
• Structural variations in Aβ fibrils may contribute to distinct pathophysiological outcomes in Alzheimer's disease and CAA.