Aβ∗56 is a stable oligomer that impairs memory function in mice.

Amyloid-β (Aβ) oligomers consist of fibrillar and non-fibrillar soluble assemblies of the Aβ peptide. Aβ∗56 is a non-fibrillar Aβ assembly that is linked to memory deficits. Previous studies did not decipher specific forms of Aβ present in Aβ∗56. Here, we confirmed the memory-impairing characteristics of Aβ∗56 and extended its biochemical characterization. We used anti-Aβ(1-x), anti-Aβ(x-40), anti-Aβ(x-42), and A11 anti-oligomer antibodies in conjunction with western blotting, immunoaffinity purification, and size-exclusion chromatography to probe aqueous brain extracts from Tg2576, 5xFAD, and APP/TTA mice. In Tg2576, Aβ∗56 is a ∼56-kDa, SDS-stable, A11-reactive, non-plaque-dependent, water-soluble, brain-derived oligomer containing canonical Aβ(1-40). In 5xFAD, Aβ∗56 is composed of Aβ(1-42), whereas in APP/TTA, it contains both Aβ(1-40) and Aβ(1-42). When injected into the hippocampus of wild-type mice, Aβ∗56 derived from Tg2576 mice impairs memory. The unusual stability of this oligomer renders it an attractive candidate for studying relationships between molecular structure and effects on brain function.