We usually think of the liver as the body’s cleanup crew, filtering harmful substances out of the blood. New research from the Keck School of Medicine of USC suggests that when this filtering system ages, it may quietly contribute to two of the most feared diseases of later life: Alzheimer’s disease and heart disease. In aged rats, an experimental drug reversed key signs of liver aging and brought blood levels of amyloid beta and LDL cholesterol back to those of young animals.

A filter whose pores close with age

The study focuses on liver sinusoidal endothelial cells (LSECs), a little-studied cell type that lines the liver’s blood vessels. These cells are dotted with tiny holes, like a sieve. The holes let larger molecules in the blood reach hepatocytes, the cells that do most of the liver’s clearance work.

With normal aging, those holes shrink and eventually close, so larger molecules stay in circulation longer. One of them is amyloid beta, the protein that forms plaques in the brains of people with Alzheimer’s disease. The researchers hypothesized that closing pores in LSECs could help explain why amyloid beta lingers in the blood with age.

What the experiment showed

The team gave aged rats cinaciguat, a drug that activates an enzyme called soluble guanylate cyclase, for two weeks. They compared them with untreated aged rats and untreated young rats. In the treated animals, the LSEC pores reopened and the cells recovered their ability to clear substances from the blood. Circulating amyloid beta dropped by half, to the level seen in young rats, while untreated aged rats showed no such decrease.

The surprise: LDL cholesterol fell too

The researchers also measured LDL, the “bad” cholesterol that builds up in arteries. LDL was meant to act as a control, because its particles are small enough to leave the blood without passing through the LSEC pores. By the original hypothesis, it should not have changed. Instead, LDL in treated aged rats dropped to young-animal levels.

That result pushed the team to look at how LSECs and hepatocytes talk to each other. They described a previously unknown signaling chain. Cinaciguat activates soluble guanylate cyclase in LSECs, which then release a growth factor called HB-EGF. HB-EGF in turn prompts hepatocytes to change their surfaces so they can grab LDL and amyloid beta from the blood. According to the study’s abstract, aged LSECs still make HB-EGF but fail to release it, and cinaciguat restores that release.

Why this is interesting

Most Alzheimer’s drug efforts target the brain, and the press release notes that such treatments have failed in clinical trials at a very high rate (98 percent, according to the release). Delivering drugs across the blood-brain barrier is also notoriously hard. The liver is a far easier target, so a liver-directed approach to lowering amyloid beta, and possibly LDL, is an attractive idea. The authors also point to HB-EGF as a potential future drug target. According to the university, this is the first study to show a drug fully restoring the shape and function of LSECs, and the first liver-directed treatment to normalize amyloid beta and LDL levels raised by aging.

What this does not show yet

Headlines saying the treatment “may help prevent” Alzheimer’s and heart disease are a hypothesis, not a result. The work was done in rats, and the outcomes reported are circulating levels of amyloid beta and LDL and the condition of liver cells, not dementia or clogged arteries. Whether lowering amyloid beta in the blood reduces amyloid in the brain or the risk of Alzheimer’s is still unproven. The senior author said further translational work is needed to learn whether the findings point to new therapies, and the team plans to keep testing in rats whether lowering amyloid beta this way actually helps prevent Alzheimer’s. Safety and effects in humans are separate questions this study does not address.

The research was led by corresponding author Laurie DeLeve, MD, PhD, with first author Sam de Leve and co-authors Xiangdong Wang, Helia Alavifard and Lily Dara, and was federally funded by the National Institutes of Health.

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