Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) peptide aggregation.
• Aβ exists as various C-terminal variants (Aβ37-Aβ43).
• The seeding potential of individual Aβ variants in AD pathology is not well understood.

Purpose of the Study:

• To investigate the relative seeding activities of different recombinant Aβ C-terminal variants (Aβ38, Aβ40, Aβ42, Aβ43).
• To determine the impact of specific Aβ variants on cerebral Aβ deposition and pathology.
• To explore the potential role of Aβ43 in the early stages of AD.

Main Methods:

• Inoculation of genetically modified App^NL-F knock-in mice with recombinant Aβ38, Aβ40, Aβ42, or Aβ43 aggregates.
• Assessment of cerebral Aβ deposition and pathology post-inoculation.
• Comparison of pathology induced by recombinant Aβ seeds versus brain-derived Aβ seeds.

Main Results:

• Aβ38 and Aβ40 aggregates did not significantly increase cerebral Aβ42 levels.
• Aβ42 aggregates increased Aβ42 levels in a subset of mice.
• Aβ43 aggregates robustly induced Aβ42 accumulation in all mice, comparable to brain-derived seeds.
• Aβ43 seeds induced a distinct cerebral Aβ pathology pattern, suggesting a unique strain.

Conclusions:

• Longer C-terminal Aβ variants, particularly Aβ43, are more potent inducers of cerebral Aβ deposition.
• Aβ43 aggregates may represent a critical factor in initiating Aβ pathology in Alzheimer's disease.
• Recombinant Aβ43 can polymerize into a distinct pathological strain.