Shirley Wu, professor of pharmacy at the University of Toronto.
A new nanoconstruct is showing promise as a way to not only diagnose Alzheimer’s disease at an early stage, but may help slow progression.
Nanoconstructs are made of nanoparticles and other molecules. Preliminary studies of this particular one show it can get past the blood brain barrier in mice, target the amyloid-beta peptides that are the hallmark of Alzheimer’s disease and improve magnetic resonance imaging (MRI).
As a bonus, it reduces inflammation and may play a role as a therapeutic – making it both a therapeutic and diagnostic, or theranostic for short, according to Shirley X.Y. Wu, professor of pharmacy at the University of Toronto. Results were published in Nano Today.
The nanoconstruct consists of several components, a significant one being manganese dioxide nanoparticles. These nanoparticles react with hydrogen peroxide in the Alzheimer’s brain, producing soluble manganese-(II) ions which work to enhance MRI contrast.
The second component of the nanoconstruct is a terpolymer which has three elements, each designed to play different roles. “That’s our intervention,” says Dr. Wu.
The first part is polysorbate-80 which helps the nanoconstruct cross the blood brain barrier. It does this by recruiting apolipoprotein from the blood and onto its surface. This coating is recognized by receptors at the blood brain barrier which then transport the nanoconstruct across.
Once the nanoconstruct passes the barrier, the second key element comes into play: an anti-amyloid-beta antibody. This antibody finds, and binds to, amyloid-beta peptides – both in plaques and soluble, free-floating molecules. Amyloid plaques are misfolded proteins found in the brains of people with Alzheimer’s disease.
“The antibody’s role is to select the target site and bind to it,” says Dr. Wu.
The terpolymer also has a feature which prevents the manganese ions from causing brain damage. This is important because water-soluble manganese-(II) ions are the key to enhancing the MRI signal. But if the concentration of manganese-(II) ions is too high, it can be toxic, says Dr. Wu.
The third element of the terapolymer binds with the soluble manganese (II) ions, reducing their toxicity. “The terpolymer consists of a carboxylic group, which binds with the manganese cationic ion via charge-charge interaction,” she says.
In addition to producing manganese-(II), the nanoparticles generate oxygen and increase the pH after reactions with hydrogen peroxide and protons. This reaction helps reduce inflammation. The oxygen also has a therapeutic benefit because tissue in the inflamed area is typically hypoxic.
Another beneficial consequence of the chemical binding is that it creates a soluble complex that travels to the cerebral spinal fluid (CSF). This helps make the imaging more sensitive, allowing the disease to be detected much earlier than is currently possible. The researchers showed this effect in three-month old living mouse models of Alzheimer’s.
Normally, at three months these mice have very early disease with little or no brain damage, and plaques are nearly impossible to detect. But using the nanoconstruct, “we can detect the CSF changes in MRI. That’s because inflammation takes place earlier than the plaque formation,” says Dr. Wu.
The researchers didn’t expect this extra aspect to signal improvement in the CSF. The next step is to further study potential toxicities in animal models before moving to human trials.
Detecting the disease early can have significant benefits, according to Dr. Josée Guimond, Interim Director, Research and Knowledge Translation and Exchange, Alzheimer Society of Canada, who was not involved in the study.
“Alzheimer’s disease starts in the brain far earlier than symptoms appear. That’s why early and timely diagnosis is crucial. With early diagnosis, people living with dementia and their families can access the care and support they need to maintain their quality of life, for longer, and make important decisions about their future,” she says.
Dr. Guimond noted there are other research projects also investigating ways to improve MR imaging, such as studies comparing images from Alzheimer’s patient brains to those of people without the disease, with the goal of identifying differences that reveal early indicators.