The interaction of insoluble Amyloid-ß with soluble Amyloid-ß dimers decreases Amyloid-ß plaque numbers.

ABSTRACT

OBJECTIVES: The heterogeneity of Amyloid-beta (Aß) plaque load in patients with Alzheimer's disease (AD) has puzzled neuropathology. Since brain Aß plaque load does not correlate with cognitive decline, neurotoxic soluble Aß oligomers have been championed as disease-causing agents in early AD. So far, investigating molecular interactions between soluble oligomeric Aß and insoluble Aß in vivo has been difficult because of the abundance of Aß oligomer species and the kinetic equilibrium in which they coexist. Here, we investigated whether Aß plaque heterogeneity relates to interactions of different Aß conformers. MATERIALS AND METHODS: We took advantage of transgenic mice that generate exclusively Aß dimers (tgDimer mice) but do not develop Aß plaques or neuroinflammation during their lifetime, crossed them to the transgenic CRND8 mice that develop plaques after 90 days and measured Aß plaque load using immunohistochemical and biochemical assays. Furthermore, we performed in vitro thioflavin T (ThT) aggregation assays titrating synthetic Aß42 -S8C dimers into fibril-forming synthetic Aß42 . RESULTS: We observed a lower number of Aß plaques in the brain of double transgenic mice compared to tgCRND8 mice alone while the average plaque size remained unaltered. Corroborating these in vivo findings, synthetic Aß-S8C dimers inhibited fibril formation of wild-type Aß also in vitro, seen by an increased half-time in the ThT assay. CONCLUSIONS: Our study indicates that Aß dimers directly interfere with Aß fibril formation in vivo and in vitro. The variable interaction of Aß dimers with insoluble Aß seeds could thus contribute to the heterogeneity of Aß plaque load in AD patients.