Study Reveals How Renegade Protein Disrupts Brain Cell Function in Alzheimer’s Disease

Dozens of molecules can be entangled with bundles of tau, a protein that normally structures nerve fibers, to cause damage to brain cells that contribute to neurodegenerative diseases, a new study shows.

Neuroscientists have previously discovered that tau can become toxic when additional chemical molecules with their structure accumulate in the brain, causing protein tangles to form that destroy surrounding tissue.

Led by researchers at New York University Grossman School of Medicine, the new study looked at the composition of such tangles and found 12 proteins that they say have not previously been linked to Alzheimer’s disease and tau. They also discovered several dozen other proteins that appear in the later stages of the disease, as well as in the early stages of dementia.

“Our findings expand our understanding of the molecular interactions that cause Alzheimer’s and other brain-damaging diseases related to tau protein misbehavior,” says study co-author Eleanor Drummond, Ph.D., research assistant professor at the NYU Langone Health Department of Neurology.

“Now that we have a better understanding of the possible ‘key players’ in neurodegeneration, we can have clearer goals for possible therapies,” says co-author Geoffrey Pires, a doctoral student in neurology at Langone University of New York.

An estimated 5 million Americans live with Alzheimer’s, a progressive disease that primarily affects people over the age of 65 and interferes with memory, language, and decision-making. Currently, there are no effective treatments or prevention strategies for Alzheimer’s. Experts have long linked it to an accumulation of additional phosphate molecules in tau proteins. However, it is not well understood how these tangles damage neurons and what other proteins are involved in the development of Alzheimer’s characteristic packages, Drummond says.

The new study, published online July 28 in the journal. Brain, provides what Drummond and colleagues say is the largest description to date of the proteins present in these tau tangles.

For the investigation, the research team analyzed donated brain tissue samples from 12 men and women with Alzheimer’s disease. After separating the tau nodes from the surrounding tissue, the researchers examined the packages to identify the many tangled proteins inside.

According to the findings, the tangles were made up of 542 different proteins in total, some of which are involved in essential processes within cells, such as energy production (vacuolar subunit-ATPase ATP6V0D1), reading of genetic material (protein of HNRNPA1 RNA binding) and cellular decomposition and digestion (PSMC 1 to 5). These results provide clues to how tangles lead to the death of neurons, Drummond says.

“Alzheimer’s has been studied for more than a century, so it is telling that we are still discovering dozens of proteins that we had no idea were associated with the disease,” says study lead author Thomas Wisniewski, MD, Gerald J . and Dorothy. R. Friedman Professor, Department of Neurology, NYU Langone.

Wisniewski, also a professor in NYU Langone’s Pathology and Psychiatry departments, plans to investigate newly identified proteins in tissue samples from people with other tau-linked neurodegenerative diseases, such as Pick’s disease and chronic traumatic encephalopathy, as well as other forms dementia