Summary: Researchers have developed a new method that uses antibody fragments encapsulated in nanomicelles that can cross the blood-brain barrier and reduce beta-amyloid levels in the brains of mouse models of Alzheimer’s disease.
Source: Tokyo Medical and Dental University
Sometimes the best things in life happen by chance, when we happen to be in the right place at the right time.
Now, Japanese researchers have found a way to ensure that new drugs are delivered to the right place in the body and at the right time of disease progression, so they have the best effect.
In a study recently published in the Journal of Nanobiotechnologyresearchers led by Tokyo Medical and Dental University (TMDU) have revealed that a new delivery system delivers treatment where it’s 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, including Aβ oligomers (AβOs).
“Several clinical trials have attempted to use an anti-Aβ antibody to treat AD, but the results have not been satisfactory,” says the study’s lead author, Akiko Amano. “A potential explanation for this is that the blood-brain barrier (BBB) blocks most full-length antibodies from entering the brain.”
To address this challenge, researchers have previously developed glucosylated (sugar-bound) polymeric nanomicelles, which are tiny hollow balls that could successfully cross the BBB by transcytosis into mouse brain capillary endothelial cells; this process was mediated by glucose-transporter-1 and induced by an increase in blood glucose after the mice experienced fasting conditions.
In this study, Takanori Yokota and colleagues filled MPs with fragments of an anti-AβO antibody, injected them into a mouse model of AD, and assessed brain and behavioral effects.
“The results were very clear,” says lead author Nobuo Sanjo. “The administration of anti-AβO antibody fragments via PM significantly reduced the amounts of various toxic Aβ species. Additionally, the Aβ plaques that formed were smaller and less dense than those seen in untreated mice.
Next, the researchers analyzed the mice’s behavior and found that mice treated with the PM filled with antibody fragments had better learning and spatial memory than untreated mice. “Our results suggest that delivery of sufficient levels of antibodies to the brain using PM can reduce toxic Aβ species and slow the progression of Alzheimer’s disease in mice,” Amano says.
Since the failure of anti-Aβ antibodies to improve cognitive function in human clinical trials was likely due to insufficient antibody supply to the brain, PM-encapsulated antibody fragments may represent an effective means of prevent the progression of AD. Additionally, new AD treatment candidates that degrade toxic Aβ and reduce their toxic effects could also be delivered to the brain using the same PM-based system.
About this Alzheimer’s disease research news
Author: Nobuo Sanjo
Source: Tokyo Medical and Dental University
Contact: Nobuo Sanjo – Tokyo Medical and Dental University
Picture: Image is in public domain
See also
Original research: Free access.
“Peripheral delivery of anti-Aβ oligomer fragment antibodies encapsulated in nanomicelles reduces various toxic Aβ species in the brain” by Takanori Yokota et al. Journal of Nanobiotechnology
Abstract
Peripheral delivery of nanomicelle-encapsulated anti-Aβ oligomer fragment antibodies reduces various toxic Aβ species in the brain
Background
Although a large body of evidence has revealed that amyloid β (Aβ), particularly Aβ oligomers, protofibrils, and pyroglutaminized Aβ, primarily participate in the pathophysiological processes of Alzheimer’s disease, most clinical trials of anti-Aβ antibody therapy have never achieved successful efficacy in human clinical trials, in part because peripheral delivery of antibody-based drugs has failed to deliver sufficient amounts of molecules in the brain. Recently, we have developed polymeric nanomicelles capable of crossing the blood-brain barrier which function as chaperones to deliver greater quantities of heavy molecules to the brain. Here, we sought to assess the efficacy of newly developed Aβ-oligomer-specific 6H4 antibody fragments encapsulated in polymeric nanomicelles on the development of Alzheimer’s disease pathology in mouse models of Alzheimer’s disease at the age of emergence of the early pathology of Alzheimer’s disease.
Results
During 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 pyroglutaminated Aβ in the brain, was been observed. In addition, immunohistochemistry indicated inhibition of Aβ plaque diameters, Aβ antibody immunoreactive areas, as well as plaque core formation. Behavioral analysis of the mouse model revealed that the polymer-6H4 fragment nanomicelle group was significantly better at maintaining long-term spatial reference memory in the water maze probe and platform tests, indicating inhibition of the pathophysiological process of Alzheimer’s disease.
conclusion
The results indicate that the strategy of reducing toxic Aβ species in dementia praecox due to Alzheimer’s disease by providing enough antibodies in the brain can modify the progression of Alzheimer’s disease.