Nanoparticles have been investigated in recent years as tools for defending the brain against neurotoxic proteins that may contribute to the onset of several different neurodegenerative disorders including Alzheimer's disease. Such proteins, in particular amyloid-beta peptides, are thought to play a role depositing fibrous plaques on the brain that damage synapses (the contact points between neurons) and lead to a decline in cognitive capabilities.



During the onset of Alzheimer's, amyloid beta collects in the brain centers that form new memories. As the disease progresses, these toxic protein fragments block neurotransmitters from reaching receptors on neurons. The promise of nanoparticles is that their capacity to mimic some biological functions as well as penetrate the blood–brain barrier will enable them to stop the growth of neuron-blocking fibrils better than drug compounds that might contain some variation of short peptides, antibodies or proteins—such as human serum albumin (HSA) protein. (There currently are no anti-Alzheimer's drugs on the market.) Whereas such compounds have been shown to interfere with fibril formation, researchers are hoping that inorganic nanoparticles can do so more effectively.



Although the nanotech approach has great potential, the challenges are many, including finding a nanoparticle material that is effective yet also biocompatible and nontoxic. Another source of controversy: some nanoparticles that have been studied, including quantum dots and carbon nanotubes, seem to actually promote or accelerate fibrillation rather than prevent it.



A multidisciplinary team of researchers from the University of Michigan at Ann Arbor (U.M.) and South Korea's Kyungpook National University claim to have resolved at least some of nanotech's shortcomings in tackling amyloid-beta peptides. In a study published online last month in Angewandte Chemie International Edition the researchers describe inhibiting amyloid-beta fibrillation using cadmium telluride (CdTe) nanoparticles with a tetrahedral shape and negative charge.



"We decided to look at how inorganic materials can affect fibrillation of amyloid peptides, which are small proteinlike structures that form extended assemblies that look like nanofibers," says Nicholas Kotov, a U.M. chemical engineering professor who led the study.



Whereas as these CdTe nanoparticles are not biocompatible and would be toxic in the body, the researchers chose them because they resemble in size, charge and behavior some of the proteins that have proved effective in blocking fibrillation.



Kotov and his colleagues also chose to work with CdTe nanoparticles because the researchers have years of experience working with this material and appreciate its self-assembly properties. Particle size and shape are important when it comes to effects on fibrillation—for example, rounded shapes (like carbon nanotubes) enhance fibrillation. When a short chain of amyloid peptides wraps around a tetrahedron-shaped nanoparticle, the nanoparticles' sharp edges distort the peptides, preventing additional peptides from attaching to the chain, Kotov says.



To test this hypothesis, the researchers combined a solution containing CdTe nanoparticles with one containing amyloid peptides and then examined the results using atomic force microscopy, transmission electron microscopy and other techniques. The nanoparticles were found to produce "strong inhibition of amyloid-beta fibrillation."



The researchers think their work offers a blueprint for the nanoscale engineering of nanoparticles from biocompatible materials with properties similar to that of CdTe nanoparticles, particularly their sharp-faceted structures. "Despite the fact that CdTe [nanoparticles] are cytotoxic and cannot be used in vivo, this model demonstrates that [nanoparticles] can reach equal or better efficiency of fibrillation inhibition than the best-known proteins," according to the study.



Kotov and his team's work is a good proof-of-concept step indicating that a nanoparticle for inhibiting amyloid-beta fibrillation can be identified, says Sara Brenner, an assistant professor of nanobioscience and assistant vice president for NanoHealth Initiatives at the University at Albany, State University of New York, College of Nanoscale Science and Engineering. "A lot of basic science research that will ultimately try to make it to clinic testing starts out with the fundamental understanding of structure and function," she adds.



Research into ways that different nanomaterials might be used in medicine is not so different from more established approaches to developing drugs and therapies that must be approved for use by the U.S. Food and Drug Administration, Brenner says. "The difference here is that when we're dealing at the nanoscale there aren't hundreds of years of medical literature and human experimentation indicating what the outcomes might be," she adds.



Kotov and his colleagues know this as well as anyone. They are now developing nanoparticles that would be both successful fibril fighters and nontoxic. They also want to better understand the behavior of nanoparticles in general when injected into the blood stream, for example how these particles are transported to the brain. This means working with medical doctors interested and invested in understanding better the effect of the nanoscale structures on the progression of Alzheimer's, Kotov says.