Purdue University researchers have developed a super-resolution “nanoscope” that provides a 3D view of brain molecules in up to ten times greater detail than traditional microscopes. This could be huge for Alzheimer’s disease research and therapy development.

In America, 40 percent of people over the age of 85 have Alzheimer’s. Symptoms typically begin 10-20 years before the patient ultimately decides to see a doctor. Alzheimer’s research has been difficult because researchers have been unable to clearly see why or how the disease starts. The new nanoscope could open the doors for this area of Alzheimer’s research.

Purdue researchers have taken 3D single molecule super-resolution images of the amyloid plaques associated with Alzheimer's disease in 30-micron thick sections of the mouse's frontal cortex. Source: Purdue University / Fenil Patel

The new nanoscope was used by Indiana University researchers to further understand the structure of plaques that build up in the early stages of the brain with Alzheimer’s. The nanoscope could pinpoint what characteristics that could be responsible for the brain damage.

Before a patient develops Alzheimer’s, amyloid plaques, individual waxy deposits, develop in the brain. These deposits interact with the cells in the brain and cause inflammation that then destroys neurons and creates memory problems. Amyloid plaques are the earliest detection of Alzheimer’s. The researchers believe that stopping the development of the amyloid plaques could be key to halting the development of Alzheimer’s.

The limited resolution of conventional microscopes and the thickness of brain tissues are the reasons that this research has been difficult in the past. These two factors make the observation of 3D morphology of amyloid plaques and how they interact in the brain difficult.

"Brain tissue is particularly challenging for single molecule super-resolution imaging because it is highly packed with extracellular and intracellular constituents, which distort and scatter light — our source of molecular information," said Fang Huang, Purdue assistant professor of biomedical engineering. "You can image deep into the tissue, but the image is blurry."

The super-resolution nanoscopes uses “adaptable optics” to overcome the issues. Adaptable optics are deformable mirrors that change shape so it can compensate for the light distortion, called an aberration. Aberration happens when light signals from single molecule travel through different parts of a cell at different speeds. The new techniques developed by both teams of researchers allowed the mirrors of the nasoscope to adjust in response to the depth of a given brain sample. The technique compensates for aberration and helps with any challenges that pop up because of the thickness of the brain tissue.

The nanoscope was tested on mice who were genetically manipulated to have Alzheimer’s. This testing found that the amyloid plaques look like tiny hairballs that entangle the surrounding tissue.

"We can see now that this is where the damage to the brain occurs. The mouse gives us validation that we can apply this imaging technique to human tissue," said Gary Landreth, professor of anatomy and cell biology at the Indiana University School of Medicine's Stark Neurosciences Research Institute.

"This development is particularly important for us as it had been quite challenging to achieve high-resolution in tissues. We hope this technique will help further our understanding of other disease-related questions, such as those for Parkinson's disease, multiple sclerosis and other neurological diseases," said Fang Huang, Purdue assistant professor of biomedical engineering.

A paper on the nanoscope and the research was published in Nature Methods.