For years, scientists have known that the gut microbiome of people with Alzheimer’s disease differs from that of healthy individuals. What remains unclear is whether these changes are caused by the disease, contribute to its development, or simply occur alongside it. The answer may not lie solely in the bacteria themselves, but also in the molecules they produce and release into the bloodstream.
Researchers may have identified one such molecule. In a study published in Nature Communications, scientists identified imidazole propionate (ImP)—a compound produced by certain gut bacteria—as a potential link between the gut microbiome and Alzheimer’s disease.
From the gut to the brain
The researchers’ hypothesis begins in the gut. Some bacteria produce ImP while metabolizing histidine, an amino acid. A portion of this compound can enter the bloodstream and circulate throughout the body.
The potential problem may occur at the brain’s protective boundaries. Experiments in the study suggest that ImP can weaken the blood-brain barrier, which normally regulates the substances that move from the blood into the brain. A weakened barrier could allow more metabolites to enter the brain, where they may interact directly with neurons.
This is significant because amyloid-beta and tau are two of the main biological features associated with Alzheimer’s disease. Amyloid-beta can accumulate into plaques between neurons, while tau can undergo abnormal changes that disrupt its function and promote the formation of damaging structures inside brain cells. Both processes are closely linked to neuronal degeneration.
In laboratory experiments, ImP appeared to worsen both processes. The researchers found that the metabolite could promote amyloid-beta plaque accumulation and increase tau modification through a process called phosphorylation.
The study proposes a chain of events: certain gut bacteria produce ImP; the metabolite enters the bloodstream; it may weaken the blood-brain barrier and reach the brain; and, once there, it may promote changes linked to amyloid-beta and tau.
However, a biologically plausible pathway does not prove that the entire process occurs in people. To investigate the relationship, the researchers first examined human data and then tested different parts of the mechanism in mice and laboratory-grown cells.
Evidence from humans and mice
The scientists analyzed blood ImP levels in 1,196 cognitively healthy adults with an average age of 61.2 years. Participants with higher concentrations of the metabolite generally had lower cognitive test scores. They also had higher levels of pTau-217, a modified form of tau used as an Alzheimer’s disease biomarker, and neurofilament light chain (NfL), a protein released when neurons are damaged. Both markers can be measured in the blood and may reveal changes in the brain before symptoms develop.
The researchers also reviewed cognitive tests and biomarker measurements collected over time. Compared with participants who had the lowest ImP levels, those with the highest levels experienced faster cognitive decline during the follow-up period.
In another set of experiments, researchers administered ImP for several months to two groups of mice genetically engineered to develop features of Alzheimer’s disease. The results suggested that the metabolite worsened disease-related changes. Some mice developed more amyloid-beta plaques, while others showed greater tau abnormalities and stronger responses from astrocytes—brain cells that help protect and maintain neural tissue.
There is no “Alzheimer’s disease bacterium”
Importantly, some bacteria capable of producing ImP are also found in healthy individuals.
“ImP-producing bacteria are present in most people, but they are not very abundant in most people,” says study co-author Federico Rey, a professor of bacteriology at the University of Wisconsin, in a statement. “But what we’ve learned over the years is that microbes don’t need to be abundant to have an effect on the host.”
Source: www.wired.com