Alzheimer’s disease affects at least 5.8 million Americans, making it the most common form of dementia. Currently, there is no cure for Alzheimer’s because scientists do not fully understand what causes the disease. However, a new study is providing insight into the molecular factors that may contribute to the progression of Alzheimer’s.
Alzheimer’s disease has long been a mystery, but a recent study from Scripps Research has brought us closer to understanding the molecular factors that may contribute to the development of the disease. Published in Advanced Science on May 21, 2024, the study used a cutting-edge technique to examine individual brain cells affected by Alzheimer’s disease. By analyzing the electrical activity and protein levels within these cells, the researchers identified new molecules associated with Alzheimer’s. This discovery raises the possibility of developing targeted drugs to effectively treat or potentially slow down the progression of the disease.In the future, there is hope for advancements in the treatment of neurodegenerative disease.
Scripps Research’s professors, including clinical neurologist Stuart Lipton, MD, PhD, protein expert John Yates, III, PhD, and bioinformaticist Nicholas Schork, PhD, worked closely together to achieve this biotechnology breakthrough.
“It was astounding to me that we were able to measure the electrical activity of a single cell at an incredibly small scale and then analyze thousands of proteins within that cell,” said Schork.In a quote by senior author Lipton, who is also the Step Family Foundation Endowed Professor and co-director of the Neurodegeneration New Medicines Center at Scripps Research, he explains that using the same cell allows for the identification of the proteins responsible for the abnormal electrical activity associated with Alzheimer’s. He also highlights the method’s ability to reveal new targets for Alzheimer’s disease and related dementias. Previous studies have indicated that specific neurons in the brains of individuals with Alzheimer’s become excessively active, transmitting stronger or more frequent electrical signals. This overactivity is believed to play a role in the development and progression of the disease.The hyperexcitability associated with Alzheimer’s contributes to cognitive decline. In a new study, Lipton and his colleagues created a method to measure individual brain cells affected by Alzheimer’s and compare them with healthy cells. Using mass spectrometry, they were able to identify levels of over 2,250 proteins in each nerve cell, working in collaboration with Yates who has expertise in this technique. This allowed for precise measurements of the electrical activity of neurons, providing valuable insight into the disease.Measuring the electrical activity of cells at the single-cell level has become possible due to recent advancements. The latest system, called single cell (sc)Patch-Clamp/Proteomics, uses a small glass tube filled with a salt solution as an electrode to measure the cell’s electrical activity and then extracts the cell for protein studies with mass spectrometry.
According to Yates, “This approach allows us to connect perturbations of electrical functions to molecular events in neurons, which is an exciting application of proteomics.”
The scientists studied the electrical patterns and protein levels of approximately 150 neurons using this method.The researchers conducted experiments to analyze the cells and then utilized computational tools, as applied by Schork, to identify connections between hyperexcitability and abnormal protein levels. They identified nearly 50 proteins that were found at different levels in hyperexcitable Alzheimer’s cells compared to healthy cells.
“Some of these proteins were already known to be linked to Alzheimer’s, but many were not,” Lipton stated.
The proteins were involved in various functions of neurons, such as controlling electrons in free radicals (redox modulators), energy metabolism, and inflammation. Fifteen of the proteins were particularly notable for having either high or low levels.Lipton’s team is conducting further research on some molecules found in neurons affected by Alzheimer’s. They also plan to broaden the use of scPatch-Clamp/Proteomics for testing potential Alzheimer’s drugs to see if they can address both the neuronal hyperactivity and abnormal protein levels. These findings will be compared with experiments on larger groups of brain cells from Alzheimer’s patients, also known as cerebral organoids or “mini-brains.” Lipton emphasizes the importance of studying how cells interact with each other in order to fully understand the dysfunction in Alzheimer’s.In a mini-brain organoid, repeating this type of study could lead to additional discoveries.
Dr. Lipton suggests that this method could also be used for drug discovery efforts related to other brain diseases.
He also states, “This new personalized medicine approach, based on the protein expression and electrical activity of a single Alzheimer’s neuron, has the potential to revolutionize drug discovery not only for this disease but also for other neurological diseases that have been behind in therapeutic advancements.”
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