Amyloid-β42 oligomeric forms: AFM nanoscale structural characterization and impact on long-term memory of young and aged zebrafish

• Nanoscale characterization of monomeric, oligomeric and protofibrillar Aβ 42 on AFM. • Brain injection of β 42 does not impact exploration in young or aged zebrafish. • Oligomeric and protofibrillar Aβ 42 hinder LTM in young or aged zebrafish. • Monomeric Aβ 42 does not impact LTM in young or aged zebrafish. The contribution of amyloid-β (Aβ) soluble forms to Alzheimer's Disease (AD) is undergoing revision and the characterization of monomeric, oligomeric and protofibrillar Aβ forms used in vivo to model AD is a critical step to ensure data interpretation. Atomic force microscopy (AFM) was used to characterize the nanoscale morphology of different Aβ 42 forms also used for cerebroventricular injection (cvi) in young (6mo) and aged (36mo) adult zebrafish behavioral and cognitive tests. On the AFM, monomeric solution deposited onto mica resulted mostly in thin filamentous structures and shorter monomeric agglomerates with heights around or below 1.5 nm, as expected for single Aβ 42 . The oligomeric form was dominated by particles with globular morphology and a few short aggregates around 1 nm high and 8–12 nm long. The protofibrillar form had micrometer-long twisted fibrils of varying diameters (4.5–10 nm) and large entangled clusters with sizes of up to several tens of micrometers. On the Open Tank used to test exploratory parameters, no differences were observed between injected animals and their age-matched controls, except for a reduced distance travelled by aged individuals that received the Aβ 42 oligomeric form. Long-term memory (LTM) for the inhibitory avoidance task was not influenced by monomers cvi, whilst oligomeric and fibrillar Aβ 42 hindered LTM formation in young and aged groups. Our findings support current views of deleterious effects of Aβ 42 soluble forms on cognition and ensures that preparations were structurally unique and within expected morphologies and dimensions.