When thinking about the organs that influence brain health, the liver is unlikely to be the first that comes to mind. Yet the two organs are more closely connected than they might appear. As well as regulating metabolism, the liver is one of the body's main filtration systems, processing blood to remove toxins and waste products — including a key protein associated with Alzheimer's disease, amyloid beta.
As the organ ages, its ability to filter substances from the blood declines, potentially allowing substances linked to age-related diseases to accumulate in circulation. Now, researchers have published a study in the Journal of Biological Chemistry that found that treating aged rats with an experimental drug called cinaciguat can restore aspects of this function, halving circulating levels of amyloid beta and reducing low-density lipoprotein (LDL) cholesterol to levels seen in younger animals.
Could restoring the liver impact a range of age-related diseases?
A connection between the liver and the brain
Laurie DeLeve’s laboratory has spent decades investigating liver sinusoidal endothelial cells (LSECs), which line the liver’s tiny blood vessels. These cells contain small openings called fenestrae that allow molecules in the blood to pass through to hepatocytes, the cells responsible for much of the liver’s metabolic and clearance activity.
As the liver ages, these openings shrink or disappear, reducing the organ’s ability to filter larger molecules from circulation. The researchers initially wanted to understand whether restoring these openings could improve the clearance of triglyceride-rich lipoproteins, which are associated with atherosclerosis.
However, their attention quickly turned to Alzheimer’s disease after they discovered that around 58 percent of circulating amyloid beta is bound to those same lipoproteins. Previous studies had also found that impaired clearance of circulating amyloid beta is associated with increased levels of the protein in both the blood and brain, suggesting that the two are closely connected.
“We figured, well, if we can restore this morphology of the cell, then we'll be able to clear these lipoproteins, and then in so doing, clear the amyloid beta that's attached to them,” Sam de Leve, the study’s first author and a researcher at the University of Southern California, told DDN.
An unexpected result reveals a second mechanism
The team used a drug known as cinaciguat to test their hypothesis because it activates soluble guanylate cyclase (sGC), an enzyme involved in regulating blood vessel function. The drug was originally developed by Bayer as a potential treatment for heart failure. However, a Phase 2b clinical trial in patients with acute decompensated heart failure was stopped early after higher doses increased the risk of hypotension.
Despite these safety concerns, the researchers were interested in whether activating the same pathway could reverse age-related changes in LSECs. They therefore treated aged rats with cinaciguat for two weeks and compared them with untreated aged rats and young controls.
“My lab had previously shown that we could use this drug to treat changes in LSECs that are very similar to those seen during aging, although in that case they occurred in disease,” Laurie DeLeve told DDN. “So, when we started investigating aging, we wanted to see whether we could use the same approach therapeutically.”
Previous studies had shown that drugs could partially restore LSEC fenestration in aging, but ours is the first to fully normalize their porosity and the amount of surface area available for sieving.
—Sam de Leve, the University of Southern California.
The treatment fully restored LSEC fenestration and also reversed age-related elevations of amyloid beta. “Previous studies had shown that drugs could partially restore LSEC fenestration in aging, but ours is the first to fully normalize their porosity and the amount of surface area available for sieving,” said Sam de Leve.
Surprisingly, however, levels of LDL cholesterol also went down, falling to levels seen in young rats. Unlike the larger triglyceride-rich lipoproteins, LDL particles are small enough to pass through the liver's blood vessel walls even when the fenestrae are reduced or lost, meaning their clearance should not depend on the size or number of these openings.
“We love that we did it. But how?” said Sam de Leve, describing the team’s reaction to the result. The unexpected finding prompted the researchers to investigate whether cinaciguat was doing more than reopening the LSECs’ pores. They discovered that the drug also restored communication between LSECs and neighboring hepatocytes.
They found that cinaciguat activated soluble guanylate cyclase in LSECs, prompting them to release a growth factor called heparin-binding epidermal growth factor-like growth factor (HB-EGF). This growth factor then acted on hepatocytes, changing their cell surfaces in ways that helped the cells take up more amyloid beta and LDL from the blood.
The researchers found that this signaling pathway also became less effective with age, but cinaciguat restored its activity. “The idea that the endothelial cell is not just some dumb pavement that the blood moves over, but that it's an active participant in its environment is something we're still really needing to understand,” said Sam de Leve.
The findings also raise the possibility of targeting the signaling pathway itself. Rather than relying on cinaciguat, researchers could investigate whether HB-EGF or downstream components of the pathway offer a more selective way to restore hepatocyte clearance.
What’s next?
The results provide a potential explanation for how age-related liver dysfunction might contribute to diseases beyond the organ itself. If the liver becomes less efficient at removing substances from circulation, those substances could accumulate elsewhere in the body or disrupt processes that help maintain tissue health.
This could have implications for several age-related diseases, but especially Alzheimer's disease. The blood–brain barrier makes it difficult to deliver treatments directly to the brain, whereas the liver offers a much more accessible therapeutic target. Improving the clearance of amyloid beta from the circulation could therefore provide another way to influence the protein's levels without needing to target the brain directly.
However, the researchers have yet to establish whether these changes in circulating amyloid beta and LDL translate into meaningful improvements in disease outcomes. They are now seeking funding for a longer-term study in rats to investigate the therapeutic potential of sGC activation and explore whether restoring LSEC function could also improve the clearance of other substances implicated in aging and disease.
For now, the findings have opened up several new questions about the liver's role in maintaining health as we age. As Sam de Leve put it, “There are many, many questions here that this research raises.”
