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Amyloid-beta (Abeta) oligomers consist of fibrillar and non-fibrillar soluble assemblies of the Abeta peptide. Tg2576 human amyloid precursor protein (APP)-expressing transgenic mice modeling Alzheimer disease produce Abeta*56, a non-fibrillar Abeta assembly that has been shown by several groups to relate more closely to memory deficits than plaques. Previous studies did not decipher specific forms of Abeta present in Abeta*56. Here, we confirm and extend the biochemical characterization of Abeta*56. We used anti-Abeta(1-x), anti-Abeta(x-40), and A11 anti-oligomer antibodies in conjunction with western blotting, immunoaffinity purification, and size-exclusion chromatography to probe aqueous brain extracts from Tg2576 mice of different ages. We found that Abeta*56 is a ~56-kDa, SDS-stable, A11-reactive, non-plaque-related, water-soluble, brain-derived oligomer containing canonical Abeta(1-40) that correlates with age-related memory loss. The unusual stability of this high molecular-weight oligomer renders it an attractive candidate for studying relationships between molecular structure and effects on brain function.

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