Pursuing Alzheimer’s Disease from the Periphery

Alzheimer’s disease is a menace. A thief of memory and life. The disease manifests after abnormal deposits of proteins, which cause plaques and amyloid-beta tangles that destroy brain function, clog the brain.

That said, the precise causes of Alzheimer’s haven’t been fully established. More recently, some researchers have become interested in peripheral organs, such as the liver, which produce toxic amyloid-beta peptides. It has been shown that drugs that reduce the liver’s production of these peptides decrease brain amyloid-beta peptide levels in mice, although these results are controversial.

The University of Pittsburgh’s Renã Robinson recently received a five-year, $1.7 million grant from the National Institutes of Health to explore novel ways of efficiently and powerfully measuring the effects of amyloid-beta protein production in organs outside the central nervous system.

“We’re looking to demonstrate and establish an approach that will allow us to evaluate processes such as energy metabolism and oxidative stress in tissues outside of the brain at various stages of Alzheimer’s disease,” says Robinson, an assistant professor of chemistry in Pitt’s Kenneth P. Dietrich School of Arts and Sciences.  Until now, most Alzheimer’s disease research has focused on the brain and central nervous system. 

In essence, Robinson and colleagues plan to significantly improve and amplify existing methods of measuring differences between normal and diseased protein samples, a field called quantitative proteomics.

“It is currently not possible to multiplex to the degree necessary for answering questions about the role of peripheral organs in Alzheimer’s disease,” Robinson says. “Examining five different organs from an Alzheimer’s mouse model, and controls from three age cohorts, generates 30 samples that would each require separate analyses. Performing this study in more than one animal for each condition, for better statistics, requires an even greater number of experiments.”

Robinson and her team have successfully demonstrated a method that can multiplex, or process, as many as 20 samples in a single analysis. She thinks that number can be increased. “We propose to develop innovative quantitative proteomics methods to measure proteins in higher numbers of samples from different tissues and conditions simultaneously,” she says. “These methods will help us get to information faster about the role of peripheral tissue changes and how they relate to changes in the brain using an Alzheimer’s disease mouse model.”

At the end of the grant period, Robinson says, she hopes to provide a tool that not only will further the understanding of how energy metabolism and oxidative stress in peripheral organs contribute to the progression of Alzheimer’s disease, but also will provide therapeutic targets outside the brain for this devastating disease.