Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain

Background Although a large amount of evidence has revealed that amyloid beta (A beta), especially A beta oligomers, protofibrils, and pyroglutamated A beta s, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-A beta antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to A beta oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology.Results During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic A beta species, such as A beta oligomers, toxic A beta conformers, and pyroglutamated A beta s in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of A beta plaques, A beta-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease.Conclusions The results indicated that the strategy of reducing toxic A beta species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.

Automated summary

Researchers developed polymeric nanomicelles capable of passing through the blood-brain barrier to deliver specific antibodies to the brain. The administration of 6H4 antibody fragments in polymeric nanomicelles for 10 weeks significantly reduced the amounts of toxic A beta species in the brain and inhibited the formation of A beta plaques. Behavioral analysis also showed an improvement in spatial reference memory in mice with Alzheimer's disease.