Targeting soluble amyloid-beta oligomers with a novel nanobody

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-beta oligomers (SA beta Os) accumulate early, prior to amyloid plaque formation. SA beta Os induce memory impairment and disrupt cognitive function independent of amyloid-beta plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SA beta O (E3) nanobody generated from an alpaca immunized with SA beta O. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SA beta Os and amyloid-beta plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SA beta O and amyloid-beta plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SA beta Os are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SA beta O nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.