Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β- and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer’s disease. A mouse study by researchers from Hokkaido University and Toppan demonstrates a new method of detecting build-up of amyloid β in the brain from biomarkers in blood samples.

The findings are published in Alzheimer’s Research & Therapy in an article titled, “Immuno-digital invasive cleavage assay for analyzing Alzheimer’s amyloid β-bound extracellular vesicles,” and led by associate professor Kohei Yuyama, PhD, at the Faculty of Advanced Life Science, Hokkaido University.

“The protracted preclinical stage of Alzheimer’s disease (AD) provides the opportunity for early intervention to prevent the disease; however, the lack of minimally invasive and easily detectable biomarkers and their measurement technologies remain unresolved,” noted the researchers.

The researchers developed a biosensing technology that can detect Aβ-binding exosomes in the blood of mice, which increase as Aβ accumulates in the brain.

When tested on mice models, the Aβ-binding exosome Digital Invasive Cleavage Assay (idICA) showed that the concentration of Aβ-binding exosomes increased with the increase in age of the mice. This is significant as the mice used were Alzheimer’s disease model mice, where Aβ builds up in the brain with age.

In addition to the lack of effective treatments of Alzheimer’s, there are few methods to diagnose Alzheimer’s. Alzheimer’s can only be definitively diagnosed by direct examination of the brain—which can only be done after death. Aβ accumulation in the brain can be measured by cerebrospinal fluid testing or by positron emission tomography; however, the former is an extremely invasive test that cannot be repeated, and the latter is quite expensive. Thus, there is a need for a diagnostic test that is economical, accurate, and widely available.

Previous work by Yuyama’s group has shown that Aβ build-up in the brain is associated with Aβ-binding exosomes secreted from neurons, which degrade and transport Aβ to the microglial cells of the brain. Exosomes are membrane-enclosed sacs secreted by cells that possess cell markers on their surface. The team adapted Toppan’s proprietary idICA to quantify the concentration of Aβ-binding exosomes in as little as 100 µL of blood. The device they developed traps molecules and particles in a sample one-by-one in a million micrometer-sized microscopic wells on a measurement chip and detects the presence or absence of fluorescent signals emitted by the cleaving of the Aβ-binding exosomes.

Clinical trials of the technology are currently underway in humans. This highly sensitive idICA technology is the first application of ICA that enables highly sensitive detection of exosomes that retain specific surface molecules from a small amount of blood without the need to learn special techniques; as it is applicable to exosome biomarkers in general, it can also be adapted for use in the diagnosis of other diseases.

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