A study in aging rats suggests that restoring the function of specialized liver cells may reduce two substances associated with age-related disease: amyloid beta, linked to Alzheimer’s disease, and low-density lipoprotein (LDL), often called “bad” cholesterol. Researchers at the Keck School of Medicine of the University of Southern California found that two weeks of treatment with the experimental drug cinaciguat restored key features of aging liver cells and reduced circulating amyloid beta by about half, while bringing LDL levels down to those seen in young rats.
Why the liver may matter in Alzheimer’s disease
Although Alzheimer’s disease primarily affects the brain, scientists are increasingly investigating how other organs may influence the disease. The liver filters the blood and removes unwanted compounds, including substances that can cause harm if they accumulate.
The USC findings suggest that restoring this natural cleaning process could offer a different approach to addressing certain age-related diseases. However, the results have so far been demonstrated only in rats. Additional research is needed to determine whether the same effects occur in humans.
“Further translational work needs to be done to see if our findings suggest potential new treatments,” said corresponding author Laurie De Reve, MD, a professor of science and vice chair for scientific affairs at the University of Southern California School of Medicine. “However, we are hopeful because the results of this study are consistent with a number of epidemiological findings showing that age is a major risk factor for Alzheimer’s disease and atherosclerosis, and that liver damage is a risk factor for Alzheimer’s disease.”
Targeting the liver could be particularly valuable in Alzheimer’s research. Efforts to develop treatments that act directly on the brain face an estimated 98% failure rate in clinical trials. One major obstacle is the blood-brain barrier, which limits the movement of substances from the bloodstream into the brain. The barrier protects the brain from harmful compounds, but it can also make it difficult to deliver some drugs.
“If the idea that the liver is affected is correct, what should we do about it?” said lead author Sam de Reve, a laboratory technician at the University of Southern California and the son of Laurie De Reve. “Rather than trying to get the drug across the tedious and difficult blood-brain barrier, we can direct the drug to the liver, an organ that is more therapeutic and certainly easier to deliver.”
Restoring the liver’s aging filter
To investigate how aging affects the liver’s ability to filter the blood, the researchers focused on liver sinusoidal endothelial cells, or LSECs.
LSECs line small blood vessels inside the liver. Unlike most blood vessel walls, they contain numerous microscopic openings that act like holes in a sieve. These openings allow larger molecules in the blood to reach neighboring hepatocytes, the liver cells that perform many of the organ’s essential functions and help remove substances from the body.
As the liver ages, the openings in LSECs gradually become smaller or disappear. This can prevent some large molecules from reaching the cells responsible for removing them, allowing more of those substances to remain in the bloodstream.
Amyloid beta is one substance affected by this change. It is a major focus of Alzheimer’s research because it can accumulate in the brain and form plaques, one of the disease’s hallmarks.
Previous observations have shown that the aging liver becomes less effective at removing amyloid beta. The researchers investigated whether the gradual closing of LSEC openings could help explain why older animals have more amyloid beta in their blood.
They treated older rats with cinaciguat for two weeks and compared them with two untreated groups: older rats and younger rats.
Cinaciguat restored the structure and function of aged LSECs, reopening their microscopic pores and improving their ability to remove substances from the blood. Amyloid beta concentrations fell by about 50%, reaching levels similar to those in young rats. The same improvement was not observed in untreated older animals.
An unexpected effect on LDL
The researchers also measured LDL. Elevated LDL can contribute to fatty deposits in the arteries, which may restrict blood flow and increase the risk of heart disease.
LDL was initially included as a comparison because the researchers did not expect it to respond to the treatment. Unlike larger molecules, LDL particles are small enough to leave the bloodstream without passing through the microscopic openings in LSECs. The scientists therefore expected cinaciguat to have little or no effect on LDL levels.
Instead, LDL levels in the treated older rats fell to levels observed in young rats.
“We said, ‘Wait, why did that fail? Obviously, there’s more to this story,’” Sam de Reve said.
The result suggested that the drug does more than reopen the liver’s aging filter. It may also restore another important aspect of liver function.
Previous studies had shown that liver cells function better when LSECs are present, so the researchers investigated how the two cell types communicate. Their work identified a previously unknown group of biochemical signals that helps regulate the liver’s ability to remove substances from the bloodstream.
How liver cells communicate
The researchers found that cinaciguat activates an enzyme called soluble guanylyl cyclase inside LSECs. This prompts the cells to release a growth factor known as HB-EGF, which signals to nearby liver cells.
In response, the liver cells alter their surfaces, enabling them to capture more LDL and amyloid beta from the blood. This could explain why both substances declined after treatment, even though they do not depend on the same filtration mechanism.
Aging typically reduces the ability of LSECs to release HB-EGF. Cinaciguat restored this signaling process, allowing the liver cells to communicate more effectively and supporting the removal of substances that tend to accumulate with age.
The discovery points to a potential target for future drugs. Instead of focusing only on reopening the physical pores in LSECs, researchers may be able to develop treatments that restore the chemical signals needed for the liver to function efficiently.
Could liver rejuvenation prevent disease?
According to the researchers, this is the first study to show that the drug can fully restore the structure and function of aged LSECs, including their ability to support the removal of substances from the bloodstream.
It is also the first to show that a liver-targeted treatment can reverse age-related increases in circulating amyloid beta and LDL to levels seen in younger animals.
The findings raise the possibility that cinaciguat, similar drugs, or treatments targeting HB-EGF could eventually counter some effects of liver aging. If these changes provide meaningful protection against disease, they could lead to new strategies for addressing Alzheimer’s disease and cardiovascular problems.
For now, however, the research remains at an early stage. Lowering amyloid beta in the bloodstream does not necessarily mean that amyloid plaques in the brain will decrease or that Alzheimer’s disease can be prevented.
The researchers plan to continue studying cinaciguat in rats to determine whether its effect on amyloid beta leads to measurable protection against Alzheimer’s disease. They also hope the findings will encourage researchers studying other diseases, particularly atherosclerosis, to examine how restoring liver function affects disease development.
“We hope that people working in fields such as atherosclerosis research will read this and want to grab some ideas for themselves,” Sam de Reve said. “There are six ways we can go about this, but we can’t do them all. So please scoop us up. We’d love to.”
Study authors and funding
Additional researchers involved in the study included Xiangdong Wang, Helia Alavifard and Lily Dara, all affiliated with the Keck School of Medicine at the University of Southern California.
The research received federal funding from the National Institutes of Health through grants R56AG071480 and 5R01DK100580.
Source: www.sciencedaily.com
