Fibronectin May Drive Blood-Brain Barrier Leaks in Alzheimer’s

The brain maintains one of the body’s most tightly controlled entry policies.

Oxygen and nutrients are allowed through. Toxins, germs and other substances carried in the bloodstream are kept out.

The blood-brain barrier regulates this access: it is a tightly closed boundary surrounding the brain’s blood vessels. In Alzheimer’s disease, however, that protective boundary can start to become permeable.

Fibronectin and blood-brain barrier damage in Alzheimer’s

Scientists may have now identified a protein that helps keep this gateway from closing. Unexpectedly, it is ordinarily part of the body’s tissue-repair machinery.

A new study in Nature Aging identifies fibronectin – a protein that supports the healing of injured tissue – as a major cause of blood-brain barrier damage in Alzheimer’s models associated with the APOE4 gene variant.

The researchers outlined a potential sequence of events. APOE4, inflammation and Alzheimer’s-related amyloid-beta cause supporting brain cells to make excessive amounts of fibronectin. This protein then builds up around blood vessels, interferes with the signals that keep them sealed and enables the barrier to leak.

Importantly, this process was reversed by the team in experimental models.

"The most direct and most translatable finding is that reducing fibronectin itself rescues the barrier defects," Columbia University neuroscientist Çağhan Kızıl told ScienceAlert.

This is significant because blood-brain barrier failure can occur early in Alzheimer’s, at times before memory difficulties emerge. When the barrier is compromised, unwanted material may enter brain tissue and inflammation may worsen.

Much Alzheimer’s research, along with several treatments, centres on amyloid-beta and tau, the proteins that create plaques and tangles in the brain. The results point towards a further possible target: safeguarding the brain’s blood vessels and sealing leaks around them.

How APOE4 may trigger fibronectin build-up

The investigation started with APOE4, the most powerful known genetic risk factor for late-onset Alzheimer’s.

Carrying APOE4 does not mean a person will develop the condition. However, one copy raises the risk, while two copies increase it even more. The variant has also been linked with early blood-brain barrier damage, although the mechanism by which it might produce a physical opening had not been clear.

Fibronectin functions as temporary scaffolding at sites of injury, providing cells with something to attach to as they repair damaged tissue. Yet in the brain, an overabundance of this scaffolding could itself become problematic.

The researchers studied post-mortem brain tissue and cerebrospinal fluid from people with Alzheimer’s. They then examined their results in human cells, three-dimensional blood-vessel models, APOE4 mice and zebrafish.

In all of these systems, fibronectin collected around blood vessels in the brain. A substantial proportion was produced by astrocytes – star-shaped cells that encircle vessels and contribute to maintaining the blood-brain barrier.

Astrocytes made more fibronectin in response to APOE4, inflammation and amyloid-beta.

The repair scaffolding was, in effect, starting to obstruct the entrance.

As fibronectin built up, it interrupted the growth signals through which astrocytes and blood-vessel cells communicate. In the absence of these messages, the junctions that seal the vessels became weaker, leaving openings that allowed material in the blood to pass out.

Yet fibronectin could simply have been accumulating around vessels that were already damaged.

To test this possibility, the team engineered support cells in zebrafish brains to generate additional human fibronectin. On its own, the protein was sufficient to cause barrier leakage.

Fibronectin was therefore not just found at the damaged site; it was contributing to the injury.

Potential ways to protect brain blood vessels

The researchers next targeted the issue at several stages. Lowering fibronectin reduced leakage in zebrafish exposed to amyloid-beta. Blocking the cell pathway by which fibronectin suppressed protective signals reactivated those signals.

In another experiment, the team inhibited VEGF signalling, which damaged the tight junctions of the blood vessels. They subsequently introduced two downstream growth factors, HB-EGF and IGF-1, and these restored tight-junction levels.

These experiments also indicated possible points at which researchers could intervene.

An earlier genetic finding makes fibronectin a particularly compelling target.

"We previously identified a rare loss-of-function FN1 variant that lowers AD risk in APOE4 carriers by 71%, with no evidence of harm in carriers – nature has already run a version of this experiment," Kızıl said.

This does not imply that fibronectin should be removed altogether. It is needed by the body for wound repair and the maintenance of blood vessels.

"That reframes the goal: not eliminating fibronectin, which the body needs for wound healing and normal vascular maintenance, but developing a way to selectively curb its pathological buildup at the brain's blood vessels," Kızıl explained.

A future antibody or small-molecule medicine could potentially remove surplus fibronectin from around these vessels. A gene-based treatment that reproduces the protective variant’s effect in the brain is another possibility.

Nevertheless, this is still mechanistic, preclinical research. The interventions have not been demonstrated to protect memory or cognition in animals, much less to treat Alzheimer’s in people.

The human results are correlational and require verification in larger cohorts. Before clinical trials can begin, scientists need to show that targeting fibronectin improves cognition in animals, confirm its safety and ensure it can reach the brain without interfering with fibronectin’s beneficial functions elsewhere in the body.

Even so, the finding adds an interesting new suspect. In Alzheimer’s, some of the problem may arise because the repair crew leaves so much scaffolding behind that the door is unable to shut.

The study was published in Nature Aging.

This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we take pride in our process, we are only human. If you notice an error, please let us know.