An experimental drug halved an Alzheimer’s-linked protein in old rats within two weeks

Two weeks of cinaciguat cut amyloid beta in the blood of aged rats by about half, down to levels seen in young rats, according to researchers at the Keck School of Medicine of USC. LDL cholesterol in the treated animals also fell to young-animal levels, a result the team had not expected. Untreated old rats showed no similar change.

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The target was the liver, not the brain.

Liver sinusoidal endothelial cells and their shrinking pores

The work, published in the Journal of Biological Chemistry with the paper “Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL,” centers on liver sinusoidal endothelial cells, which line the liver’s smallest blood vessels and carry microscopic pores called fenestrations. In aging, those pores shrink or vanish, so large molecules such as amyloid beta are cleared less efficiently. Laurie DeLeve, a professor and vice chair for scientific affairs in USC’s Department of Medicine and the corresponding author, led a team that included first author Sam de Leve, Xiangdong Wang, Helia Alavifard and Lily Dara.

Researchers gave aged rats cinaciguat for two weeks and compared them with untreated old and untreated young animals. The drug restored the cells’ structure and function, reopened the pores and improved clearance of substances from the blood.

Funding came from the National Institutes of Health, under grants R56AG071480 and 5R01DK100580. The corresponding author’s affiliation and the grant numbers are listed in the journal record, which makes the study traceable to a named institution and a federal funder rather than to a company with a drug to sell.

The three-group design carries the study’s logic: treated old rats, untreated old rats and untreated young rats. Treated animals matched the young group on amyloid beta and LDL while untreated old animals did not, so the difference can be attributed to the drug within that design. Animal numbers, ages and doses are not given in the summaries, and the full text would be needed to judge statistical power.

Soluble guanylate cyclase, HB-EGF and the hepatocyte hand-off

Cinaciguat activates soluble guanylate cyclase in the sinusoidal cells. That prompts the cells to release a growth factor, HB-EGF, which signals neighboring liver cells, the hepatocytes, to change their surfaces so they capture more LDL and amyloid beta from circulation. Aging normally impairs the HB-EGF release, and the drug restored it. The USC press release, dated October 27, 2026, describes the mechanism the same way.

Sam de Leve said the idea is to direct drugs to the liver rather than trying to get a drug through the blood-brain barrier, which he called obnoxiously difficult. He said the LDL drop prompted a double take in the lab, since LDL particles are small enough to pass without the pores, and that the team hopes researchers in fields such as atherosclerosis research will pick up the idea. The authors suggest future drugs could target this chemical signaling, not only the physical pores.

The unexpected cholesterol result shaped how the team framed the work. The press release ties the findings to preventing both Alzheimer’s and heart disease, and the authors hope atherosclerosis researchers will take up the signaling idea for themselves. LDL particles are small enough to slip through the liver’s pores, so the drug’s effect on LDL points to the hepatocyte hand-off, rather than pore size alone, as the active ingredient.

Heart disease is part of the pitch. The Keck release says the treatment may help prevent Alzheimer’s and heart disease, a claim the researchers qualify by saying the lab result has not yet been tested for either outcome in an animal that develops disease.

Cinaciguat’s earlier life as a heart failure drug

Cinaciguat is not new to medicine. Bayer developed it as BAY 58-2667 for acute decompensated heart failure, and a PubMed review of the compound describes a potent vasodilator that reduced cardiac load and raised cardiac output in early human trials, while cautioning that those studies were not sufficient to establish efficacy and safety. Nothing in the USC reports says the rat dose or schedule would transfer to people, and the press release gives no doses.

The caveats are stated by the team. Lower blood amyloid beta does not necessarily mean fewer plaques in the brain or protection against Alzheimer’s, and the ScienceDaily summary notes that the next step is further rat studies to test whether the amyloid effect translates into protection. Brain-directed Alzheimer’s drugs have an estimated 98% clinical-trial failure rate according to the university, which is the stated motivation for looking elsewhere. The Alzheimer’s Association counts more than 7 million Americans with the disease. DeLeve said further translational work is needed to see whether the findings point to new therapies.

The amyloid beta measured here is the protein circulating in blood, produced throughout the body and cleared in large part by the liver. That is the logic for aiming at the liver: improve the body’s own clearance and let the blood-brain barrier problem go unsolved. Whether circulating levels in rats track brain deposits, and whether lower blood levels slow any disease process, is the experiment the team has said comes next.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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