Summary: Researchers have developed a new method that uses antibody fragments encapsulated in nanomicelles which can cross the blood-brain barrier and reduce levels of amyloid-beta in the brains of mouse models of Alzheimer’s disease.
Source: Tokyo Medical and Dental University
Sometimes the best things in life come by chance, when we happen to be in the right place at the right time.
Now, researchers from Japan have found a way to ensure that new medications are delivered to the right place in the body and at the right timepoint in disease progression, so that they have the best effect.
In a study published recently in the Journal of Nanobiotechnology, researchers led by Tokyo Medical and Dental University (TMDU) have revealed that a novel delivery system delivers treatment to where it is needed most in a mouse model of Alzheimer’s disease (AD).
AD is a common neurodegenerative disease that causes dementia. It is characterized by the accumulation of a protein called amyloid β (Aβ) in the brain, and a number of different toxic forms of Aβ have been identified that impair brain function, notably Aβ oligomers (AβOs).
“Multiple clinical trials have attempted to use an anti-Aβ antibody to treat AD, but the results have been unsatisfactory,” says lead author of the study Akiko Amano. “One potential explanation for this is that the blood–brain barrier (BBB) prevents most full-length antibodies from entering the brain.”
To address this challenge, the researchers previously developed glucosylated (sugar-linked) polymeric nanomicelles (PMs), which are tiny, hollow balls that could successfully cross the BBB via transcytosis in mouse brain capillary endothelial cells; this process was mediated by glucose-transporter-1 and induced by an increase in blood glucose levels after the mice experienced fasting conditions.
In this study, Takanori Yokota and colleagues filled PMs with fragments of an anti-AβO antibody, injected them into a mouse model of AD, and assessed the effects on the brain and on behavior.
“The results were very clear,” explains senior author Nobuo Sanjo. “Administration of anti-AβO antibody fragments through PMs significantly reduced the amounts of various toxic Aβ species. In addition, the Aβ plaques that did form were smaller and less dense than those seen in untreated mice.”
Next, the researchers analyzed the behavior of the mice and found that the mice treated with the antibody fragment-filled PMs had better learning and spatial memory than untreated mice. “Our findings suggest that delivering sufficient levels of antibodies to the brain using PMs can reduce toxic Aβ species and slow AD progression in mice,” says Amano.
Given that the failure of anti-Aβ antibodies to improve cognitive function in human clinical trials was likely because of an insufficient supply of the antibodies in the brain, PM-encapsulated antibody fragments could represent an effective way to prevent AD progression. In addition, new candidates for AD treatment that degrade toxic Aβs and reduce their toxic effects could also be delivered to the brain using the same PM-based system.
Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain
Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer’s disease, most clinical trials of anti-Aβ 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 Aβ 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.
During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-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.
The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimer’s disease by providing sufficient antibodies in the brain may modify Alzheimer’s disease progression.