Alzheimer’s disease impacts around 200,000 Americans; it is the country’s sixth leading cause of death. The disease is thought to begin affecting the brain ten to twenty years before it can be diagnosed, which is a serious treatment challenge. New work by scientists at Purdue University may change that. They have found a way to assess molecules in the brain with much greater detail; the technique could help researchers learn how the disease progresses, and where therapeutics could be applied. The work has been reported in Nature Methods.
Amyloid plaques are known to build up before Alzheimer’s disease starts in the brain. The clumps inflame cells, which can destroy neurons and impair memory. Plaque buildup is the first symptom of the disease. The nanoscope the researchers created helped them view plaques in Alzheimer’s patients.
"While strictly a research tool for the foreseeable future, this technology has allowed us to see how the plaques are assembled and remodeled during the disease process," explained Gary Landreth, professor of anatomy and cell biology at the Indiana University School of Medicine's Stark Neurosciences Research Institute. "It gives insight into the biological causes of the disease so that we can see if we can stop the formation of these damaging structures in the brain."
Slices of brain tissue are often thick, and there are limitations with conventional light microscopes. That has prevented investigators from making good observations of amyloid plaques and their behavior.
"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 nanoscope Huang’s team made uses adaptable optics, which uses deformable mirrors to compensate for aberrations created by light. To apply it to brain tissue, the scientists found ways to make adjustments to the mirrors as the microscope penetrates different depths of tissue. Their methods boost the signals coming from molecules.
With this nanoscope, researchers get viewing resolution that is six to ten times than what conventional tools achieve. The team could then use an Alzheimer’s mouse model to look at huge brain sections and the plaques within them. Amyloid plaques act like a kind of hairball, entangling the tissues around it with small fibers that extend from the accumulated wax.
"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," Landreth said.
The researchers are already using the nanoscope to look at amyloid plaques; they also are studying their effect on cells, and how they change.
"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," Huang said.