Experimental drug reverses liver aging, reduces Alzheimer’s protein in rats

The findings, published in the Journal of Biological Chemistry, also revealed a previously unknown communication pathway between liver cells. This discovery suggests the potential to develop therapies that enhance the liver’s ability to remove harmful substances from the blood, potentially mitigating the risk of Alzheimer’s disease and atherosclerosis.

The liver’s role in filtering the blood and removing unwanted compounds makes it a growing area of interest in Alzheimer’s research. Restoring this natural cleaning process may offer a new approach to preventing age-related illnesses. However, the results have only been demonstrated in rats, and further study is needed to determine if the benefits extend to humans.

“We need to do further translational work to see whether our findings might point to new therapies,” said Laurie DeLeve, MD, PhD, professor and vice chair for scientific affairs in the USC Department of Medicine. “We’re hopeful, though, because the findings line up with a lot of epidemiological results showing age as a major risk factor for Alzheimer’s and atherosclerosis, and liver damage as a risk factor for Alzheimer’s.”

Researchers theorize that targeting the liver could bypass challenges associated with delivering drugs directly to the brain, which has a limited barrier. “Rather than trying to get a drug through the blood-brain barrier, which is obnoxiously difficult, we could direct drugs to the liver, an organ where there might be more therapeutic impact and certainly an easier job of drug delivery,” explained Sam de Leve, MA, a USC lab technician and child of Laurie DeLeve.

The study focused on liver sinusoidal endothelial cells (LSECs), which form the lining of tiny blood vessels and contain microscopic openings that allow larger molecules to reach neighboring cells. As the liver ages, these openings shrink, hindering the clearance of substances like amyloid beta.

Administering cinaciguat to aged rats for two weeks restored the structure and function of the LSECs, reopening their pores and improving their ability to clear substances. Amyloid beta concentrations decreased by approximately 50%, matching levels in young rats. The researchers also observed a surprising decrease in LDL levels.

The unexpected reduction in LDL led to the discovery of a previously unknown signaling pathway where cinaciguat activates an enzyme, triggering the release of a growth factor (HB-EGF) from LSECs. This signal then alters the surfaces of hepatocytes, allowing them to capture more LDL and amyloid beta from the blood, explaining the reduction of both substances.