A harmful form of the tau protein, which builds up in Alzheimer’s disease and similar brain disorders, can directly damage blood vessels in the brain, according to a new study by researchers at the Lewis Katz School of Medicine at Temple University. It does this by changing how the cells lining the blood vessels produce energy, which leads to inflammation and makes the blood-brain barrier – the brain's protective shield – weaker.
The discovery, reported online in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, uncovers a novel molecular mechanism that potentially explains tau-mediated vascular dysfunction in the brain and highlights the importance of focusing on early neurovascular changes mediated by tau to help prevent or slow down damage to the blood-brain barrier in Alzheimer’s disease.
“Tau has long been known to be associated with neuronal dysfunction in the brain in Alzheimer’s disease and other neurological disorders, but recent studies have shown that the protein also accumulates along the walls of brain vessels in these conditions,” explained Silvia Fossati, PhD, interim director of the Alzheimer's Center at Temple and associate professor of Neural Sciences and Cardiovascular Sciences at the Lewis Katz School of Medicine, and senior author on the new report.
Problems with blood vessels in the brain are recognized as some of the earliest changes that can lead to memory loss and other symptoms in Alzheimer’s disease and other forms of dementia. These problems generally center around the neurovascular unit—a group of different cell types, including blood vessel cells, support cells, and neurons—that work together to keep the brain healthy. This system helps regulate blood flow in the brain, controls how nutrients and energy are delivered, and helps protect the brain from inflammation and harmful substances.
Until now, scientists did not fully understand what tau protein aggregates were doing at the brain’s blood vessels. To uncover the mystery, Dr. Fossati and graduate student Roberto Guzmán-Hernández, first author on the paper who carried out the research as part of his PhD thesis, ran a series of experiments in vitro using a cell model that mimics the brain’s protective barrier. When they exposed the cells to protofibrillar tau—a form of tau that appears early in Alzheimer’s disease—they discovered that it weakened the barrier, making it more "leaky" and less able to protect the brain.
They also found that right after exposure to protofibrillar tau, brain blood vessel cells quickly changed how they make energy. This shift triggered inflammation and weakened the protective barrier, suggesting these damaging changes happen very early in the disease process.
“Up to now, the effects of tau on the cells that line the inside of these vessels were mostly understudied. We hope to have unveiled a piece of the complex mechanism leading to [tau] pathology,” said Dr. Guzmán-Hernández.
Drs. Fossati and Guzmán-Hernández confirmed their results in a mouse model, in which animals were engineered to accumulate tau in the brain, producing a condition similar to Alzheimer’s in humans. Their studies of mouse brain vasculature cast light on the mechanism by which tau protein can damage the blood brain barrier early in disease.
“Our findings highlight molecular mechanisms and metabolic changes through which fibrillar tau species contribute to a loss of barrier resistance and damage the endothelial barrier, increasing its permeability and inflammatory activation,” Dr. Fossati said.
Dr. Fossati plans next to investigate the mechanisms underlying tau entry into endothelial cells and the induction of glycolysis in the blood brain barrier. “We also are interested in better understanding the effects of protofibrillar tau on the neurovascular unit, particularly on glial cells, which support neurons in the brain,” Dr. Fossati said. “Ultimately, we hope to identify potential targets for therapeutic interventions against Alzheimer’s disease and other conditions involving neurovascular pathology.”
Funding for the study was provided by grants and awards from the National Institutes of Health, including the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging, and by the Pennsylvania Department of Health Collaborative Research on Alzheimer’s Disease (PA Cure).