Scientists from two labs conducting independent investigations found that altering gut bacteria with a drug derived from seaweed could impact the progression of Alzheimer’s disease. These studies showed that sodium oligomannate (GV-971) reduced amyloid plaques and brain inflammation in mouse models of Alzheimer’s disease, but only in male mice. The compound, which changed the gut microbiome, demonstrates a critical link between the gut and Alzheimer’s disease pathology, underscoring the importance of gut health in neurological diseases and the development of sex-specific therapies.

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A founding principle of Cure Alzheimer’s Fund is that funded researchers meet regularly to collaborate and share their findings. This fosters connections and allows researchers to benefit from the input of their peers. These gatherings aim to accelerate the advancement of discoveries and the growth of knowledge. It was during one of these meetings that Dr. Sangram Sisodia of the University of Chicago and Dr. David Holtzman of Washington University in St. Louis realized they were investigating the same compound with shockingly similar findings.

Sodium oligomannate, or GV-971, was first discovered by the Chinese pharmaceutical company Shanghai Green Valley Pharmaceuticals. Derived from brown seaweed, studies in China showed that GV-971 in mouse models reduced amyloid beta levels in the brain and lowered levels of neuroinflammation. In clinical trials with early Alzheimer’s disease patients, GV-971 appeared to stop cognitive decline. China has approved GV-971 for use in mild to moderate Alzheimer’s patients.

When approached by the Chinese scientists to evaluate and comment on their results, Dr. Sisodia was hesitant. “I made it very clear I was suspicious from the start,” Dr. Sisodia said. “You have to convince me this is true because it is so remarkable.”

This challenge led Dr. Sisodia to investigate GV-971 in his lab at the University of Chicago. “That’s what we do in science,” Dr. Sisodia explains. “We try to replicate amazing findings.” Unbeknownst to Dr. Sisodia, David Holtzman’s lab at Washington University in St. Louis had also taken on the challenge of determining if GV-971 could live up to its claims.

Thus, in separate labs using different mouse models at various stages of the disease, the two labs began the rigorous process of testing GV-971.

Dr. Sisodia’s lab used APPPS1-21 mice, a mouse model that mimics the buildup of amyloid beta (amyloidosis) in human brains during Alzheimer’s disease. The mice were treated daily with one of three doses of GV-971. Treatment began when amyloid beta levels became detectable in the brain and continued until levels were near maximal.

Dr. Holtzman’s lab used a different mouse model of amyloidosis (5xFAD) and only one dose, given daily beginning when the amyloid burden in the brain was near its peak. Both labs carried out their experiments using male and female mice.

Upon completion of the treatment protocols, the two labs looked at how GV-971 affected amyloid beta levels in the brain, neuroinflammation, and the gut microbiome. Both labs found that GV-971 treatment dramatically reduced amyloid pathology and neuroinflammation. However, these effects were only in the male mice. They also found significant changes in the composition and abundance of several types of gut bacteria in male mice. The female mice experienced minor changes in the gut microbiome.

“Who could imagine that independent labs would come up with the same results using different mouse lines and different timings of delivery of the drug?” Sisodia marveled. “Everything was different, except there was the same drug.”

Digging deeper, the labs found that GV-971 impacted microbiome metabolism and reduced inflammation in the brain and throughout the rest of the body. The reduction in brain inflammation was due to the dampening of microglial activation. Microglia are the brain’s resident immune cells. In their homeostatic state, microglia surveil the brain, looking for signs of damage or distress. When they encounter a trigger, such as amyloid plaques, microglia morph into a reactive state, causing inflammation. Once the threat is addressed, microglia return to a homeostatic state, and inflammation dissipates. However, in Alzheimer’s disease, microglia get stuck in a reactive state, causing chronic neuroinflammation, ultimately damaging the brain. GV-971 decreased the number of reactive microglia and increased the number of microglia that could revert to their homeostatic state.

This work adds to the increasing evidence of a connection between the gut microbiome, neuroinflammation, and Alzheimer’s pathology. GV-971 appears to target the microbiota-microglia-amyloid axis to lower amyloid levels in the brain and decrease neuroinflammation. This study is the first to provide evidence that GV-971 operates in a sex-specific manner. Researchers have yet to determine how GV-971 accomplishes this. The next steps involve recreating the effects of GV-971 in the gut microbiome without the drug to see if the same changes occur in the brain.

Published in Molecular Neurodegeneration

Oleg Butovsky, Ph.D., Brigham and Women’s Hospital/Harvard Medical School

Rudolph Tanzi, Ph.D., Massachusetts General Hospital/Harvard Medical School

David M. Holtzman, M.D., Washington University School of Medicine in St. Louis

Sangram S. Sisodia, Ph.D., University of Chicago