Brain’s protective barrier gets leakier with age

Time can wear down the sturdiest walls, even the one that protects the brain from bad stuff in the blood. This blood-brain barrier breaks down with age, possibly playing an important role in Alzheimer’s disease, a new study suggests.

Images published in the Jan. 21 Neuron show direct evidence that aging influences the breakdown of the blood-brain barrier and that accelerated deterioration could contribute to learning and memory problems later in life.

Researchers in California detected the deterioration in high-resolution MRI scans of the brains of living humans. Younger brains weren’t as leaky as older brains, specifically in regions critical for learning and memory, the images showed. They also revealed that older people with slight memory and learning difficulties had significantly more blood-brain barrier deterioration than healthy people of similar ages.

“This is a major advance,” says Costantino Iadecola, a neuroscientist at the Weill Cornell Medical College in New York City. Previous studies had suggested a link between aging and memory problems and blood-brain barrier breakdown, but that connection had never been shown in the brains of living people. “Now it has, and we have to put this thing back up on the board as a factor contributing to dementia,” Iadecola says.

The blood-brain barrier is made of sets of cells that zip tightly together around blood vessels in the brain. This tightly sealed layer creates a nearly impenetrable fortress that keeps potential toxins in the blood out of the brain. Tracking whether certain compounds make their way through this fortress offers clues to its leakiness and level of decay.

A group led by neuroscientist Berislav Zlokovic of the University of Southern California in Los Angeles tracked the chemical element gadolinium in MRI brain scans. Imaging the brains of healthy people ages 23 to 91 showed that the blood-brain barrier’s leakiness first appeared in the hippocampus, a region critical for learning and memory, and was greater in older brains. The disintegration was also up to 53 percent greater in parts of the hippocampi of people ages 55 to 85 who had mild difficulties with learning and memory compared with those parts in healthy people similar in age.

“Focusing on the damage of the blood-brain barrier shows that it is an important factor possibly initiating changes in the brain that lead to dementia,” Zlokovic says.

His team also showed that the breakdown of the blood-brain barrier was linked to damage to pericyte cells, which are part of the protective wall between the blood and the brain. These cells usually collect a protein called platelet-derived growth factor β, which enables them to divide and safeguard the brain. The images showed that more leakage in the blood-brain barrier was associated with more of the protein in the brain, suggesting that damaged pericytes didn’t collect the protein, but let it pass into the brain instead. People with mild memory and learning problems had 115 percent more of the protein in their brains than healthy people of similar age, the team reports.

Cultures of pericyte cells also shed the protein when exposed to a lack of oxygen or high levels of peptide plaques called amyloid-beta, which have both been linked to Alzheimer’s disease. The results suggest that aging may lead to damage to pericytes, which may ultimately be the cause of the disintegration of the blood-brain barrier.

“This is very important work,” says clinical neuroscientist Gary Rosenberg of the University of New Mexico in Albuquerque. What still needs to be determined, he notes, is at what stage in the development of dementia due to Alzheimer’s disease these changes in the blood-brain barrier occur.

It’s now the classic chicken-or-egg problem, Iadecola says. Alzheimer’s disease could lead to the buildup of amyloid-beta and damage the blood-brain barrier. Or the barrier could break down first, contributing to the buildup of the plaque and the development of dementia. The next step, he says, would be to look at the deterioration of the blood-brain barrier in people at different stages in Alzheimer’s and see if changes to the protective wall happen before or after the spread of amyloid plaques associated with the disease.