Alzheimer’s Disease May Be Triggered By Vascular System Alterations

A plasma component normally involved in blood clotting and inflammation may play a role in the development of Alzheimer’s disease in some patients, scientists at Rockefeller University report.

This is not the first time the condition has been linked to the vascular system. Yet it’s still not clear precisely how changes in the blood might spur Alzheimer’s disease (AD).

Sidney Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics at Rockefeller, said:

“There’s a lot of evidence that exercise, which helps keep your blood vessels healthy and blood flow consistent, can be protective against AD. In addition, we know that diseases that compromise the vascular system, like diabetes, put people at higher risk.”

The latest study from Strickland’s lab offers a clue and a possible path to early diagnosis and new drugs.

Plasma Protein Factor XII

The plasma protein, called Factor XII, is part of a cascade of enzymes that induces blood coagulation and inflammation. Previous studies from Strickland’s lab had shown that this cascade can be activated by beta-amyloid, a molecule that forms sticky plaques in the brains of Alzheimer’s patients.

Other research had demonstrated that the process might be overly active in the disease.

Because people with AD don’t show cognitive problems until their disease is quite advanced, it’s been difficult to study what’s transpiring in the brain at the earlier stages. But in recent years, genes linked to an early-onset hereditary form of the disease have been found, and researchers have been able to study what’s happening in the brains of people genetically predetermined to develop Alzheimer’s, even before they show any symptoms.

“It’s a devastating disease to have,” Strickland says about this inherited form of AD, “but it’s given us new research opportunities. The first changes observed in these patients are in beta-amyloid levels. The second changes are brain abnormalities related to the vascular system, which can occur 20 years before overt cognitive symptoms appear.”

Zu-Lin Chen, a senior research associate in the Strickland lab, said:

“We speculated that activation of Factor XII by beta-amyloid could play a role in initiating Alzheimer’s. That’s not something you can study in humans, so we looked at mouse models of disease to see what happens when Factor XII is knocked down.”

Alzheimer’s Disease Mice

To take out Factor XII, the team used a molecule that prevented the gene from making the protein.

Normally, Alzheimer’s disease mice show much greater neuroinflammation than healthy mice. However, AD mice whose Factor XII had been knocked down had much less inflammation than untreated AD mice and had brains that were more similar to those of healthy mice.

In addition, behavioral studies of AD mice with reduced Factor XII showed that their cognitive function improved. In one test, the mice were introduced to a maze with an escape hole.

The animals learn the location of the hole by remembering visual cues around the maze, allowing them to escape through the hole on subsequent visits. Unlike normal mice, AD mice are unable to remember where the hole was located.

Knocking down Factor XII helped.

AD mice lacking the protein learned to find their way quicker than the untreated AD mice, although their memory wasn’t as good as that of normal mice. These and other findings in the study point to one potential factor in initiating AD, though the researchers caution they may not lead to new drugs anytime soon.

“We need to further define what’s going on, so we can identify patients with vascular problems and develop a targeted therapy to help that aspect,” Chen says. “We had great improvements in our mice but we didn’t fully correct the problem. Alzheimer’s is a complex disease, and there are multiple elements involved.”

The work was supported by the National Institutes of Health; Cure Alzheimer’s Fund; Rudin Family Foundation; Mellam Family Foundation; Louis Herlands; John A. Herrmann Jr.; Mary & James G. Wallach Foundation; and Loewenberg Family Philanthropic Fund at New York Community Trust.

Image: Brain of a mouse with Alzheimer’s disease, with inflammatory cells lit up in red when activated (left). These cells become less active when Factor XII is removed (right). Credit: Laboratory of Neurobiology and Genetics at The Rockefeller University

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