Scientists discover new molecular driver of Alzheimer's disease

In a study published in 2011, Cutting-edge scienceMay 21, 2024 Researchers used a new technique to study single, living brain cells affected by Alzheimer's disease. By measuring the electrical activity of single neurons and protein levels within those neurons, scientists discovered new molecules related to Alzheimer's disease. It is hoped that in the future, these molecules will become drug targets to treat or slow the progression of neurodegenerative diseases.

Close collaboration with Scripps Research faculty, including clinical neurologist Stuart Lipton, MD, protein expert John Yates III, PhD, and bioinformatician Nicholas Schock, PhD, associate director of the Institute for Translational Genomics (TGen) and distinguished professor of Quantitative Medicine, enabled the scientists to develop this feat of biotechnology.

“It was amazing to me that we could take a single cell, measure its electrical activity at a millionth of a millionth of an ampere, and then look at thousands of proteins within the same cell to find the protein that causes the abnormal electrical activity associated with Alzheimer's,” says lead author Lipton, the Step Family Foundation Endowed Professor and co-director of the Center for New Neurodegenerative Drugs at Scripps Research Institute. “But the beauty of this approach is that it could help us discover new targets for Alzheimer's disease and related dementias.”

Previous research by Lipton and his colleagues has shown that certain neurons in the brains of people with Alzheimer's become overactive, sending stronger or more frequent electrical signals than normal. Evidence suggests that this overactivity (also known as hyperexcitation) contributes to the cognitive decline associated with Alzheimer's.

In the new study, Lipton and his colleagues developed a system that allows scientists to precisely measure individual brain cells and compare cells affected by Alzheimer's to healthy ones. Lipton's group, which previously developed a way to precisely measure the electrical activity of neurons, collaborated with Yates to use mass spectrometry to identify the levels of more than 2,250 proteins within each nerve cell. Mass spectrometry can identify and quantify proteins from cells, but these analyses have traditionally been performed on large numbers of cells. Recent advances have enabled measurements at the single-cell level.

A newer system, called single-cell (sc) patch clamp/proteomics, uses tiny glass tubes filled with salt solution as electrodes to measure the electrical activity of cells, which are then extracted for protein studies by mass spectrometry.

“This approach allows us to link disturbances in electrical function to molecular events within neurons, which is an exciting application of proteomics,” Yates says.

The scientists analyzed the electrical patterns and protein levels of about 150 neurons, and then, using computational tools applied by Shukok, discovered the link between hyperexcitability and abnormal protein levels: They identified about 50 proteins that were present at higher or lower levels in hyperexcitable Alzheimer's cells compared to healthy cells.

“Some of these proteins were already known to be associated with Alzheimer's disease, but many were not,” Lipton says.

These proteins are involved in a variety of neuronal functions, including electronic regulation of free radicals (redox regulators), energy metabolism, and inflammation. Fifteen proteins were found to be at particularly high or low levels in Alzheimer's neurons, and Lipton's group plans to follow up on some of these molecules.

He also plans to expand the use of scPatch-Clamp/Proteomics for drug screening, testing whether potential Alzheimer's drugs would correct both neuronal hyperexcitability and abnormal protein levels. He is linking these findings to experiments with larger groups of brain cells called brain organoids, or “mini-brains,” taken from Alzheimer's patients.

“One cell doesn't always tell the whole story,” Lipton explains. “Part of the dysfunction in Alzheimer's has to do with how cells interact with each other, so if we can replicate this type of study in mini-brain organoids, we may be able to discover more.”

Lipton points out that this method could also be applied to drug discovery research for other brain-related diseases.

“This new personalized medicine approach based on the protein expression and electrical activity of single neurons in Alzheimer's has the potential to revolutionize drug discovery not only for this disease but also for other neurological disorders, where other therapeutic areas are lagging far behind,” he added.