Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

Alzheimer disease (AD) is characterized by amyloid-beta accumulation, with soluble oligomers (A beta o) being the most synaptotoxic. However, the multivalent and unstable nature of A beta o limits molecular characterization and hinders research reproducibility. Here, we characterized multiple A beta o forms throughout the life span of various AD mice and in post-mortem human brain. A beta o exists in several populations, where prion protein (PrPC)-interacting A beta o is a high molecular weight A beta assembly present in multiple mice and humans with AD. Levels of PrPC-interacting A beta o match closely with mouse memory and are equal or superior to other A beta measures in predicting behavioral impairment. However, A beta o metrics vary considerably between mouse strains. Deleting PrPC expression in mice with relatively low PrPC-interacting A beta o (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrPC-interacting A beta o (APP/PSEN1). These findings highlight the relative contributions and interplay of A beta o forms in AD.