Feb. 1, 2002 Fibers known to be important in Alzheimer’s disease also are produced by bacteria that cause ailments such as urinary tract infections, according to research at Washington University School of Medicine in St. Louis. The finding is described in the February 1 issue of the journal Science.
Scott J. Hultgren, Ph.D., the Helen Lehbrink Stoever Professor of Molecular Microbiology, led the study; Matthew R. Chapman, Ph.D., post-doctoral fellow in molecular microbiology was first author.
The scientists found that certain strains of the bacterium Escherichia coli (E. coli) produce amyloid fibers similar to those that can accumulate in the brain to form senile plaques, a hallmark of Alzheimer’s disease. The bacterial fibers, known as curli, form a meshwork around the bacteria, joining them together in clusters or communities known as biofilms. Bacteria in biofilms are more resistant to antibiotics and to the body’s immune defenses.
The discovery marks the first time that amyloid has been found in bacteria. Previously, amyloid was thought to be made only by cells of higher organisms. Even then, their presence was regarded as a mistake, a biological error.
“This is the first example of a dedicated molecular machinery to produce amyloid and thus shows that amyloid production is not always a mistake,” says Hultgren. “This finding gives us a powerful genetic system to study the molecular details of amyloid formation and may allow us to begin designing drugs that will block the formation of amyloid or treat or prevent human amyloid diseases.”
Salmonella bacteria also produce bacterial amyloid or curli, and the genes for curli production exist in other bacteria, as well, says Chapman. The process of curli production is similar to the formation of a snowflake on a dust particle. The particle is a nucleus that triggers the precipitation of ice crystals at its surface, setting off a chain reaction that leads to more ice crystals and growth of the snowflake.
Curli production in E. coli involves two main proteins, CsgA and CsgB. The A protein is released by the bacteria dissolved in the surrounding fluid. The B molecule is embedded in the wall of the bacterium and is exposed to the outside. Like dust particles in snowflake production, each B protein is a nucleus that triggers the precipitation of dissolved A-proteins. As the A proteins pop out of solution they join together and align into curli fibers, with each fiber attached to a B protein.
The finding also raises the important question of whether bacterial infections play some role in amyloid diseases, including Alzheimer’s disease.
Human amyloid diseases also are thought to involve dissolved amyloid proteins that undergo a change in shape and aggregate into fibers, says Hultgren. When those fibers develop in the brain, it leads to Alzheimer’s disease. According to Hultgren, “the question is, what causes the soluble protein in human disease to convert into amyloid fibers? We can now study that mechanism in E. coli.”
Hultgren and Chapman speculate that bacterial infections could play a role in the development of amyloid plaques in Alzheimer’s disease and other amyloid diseases in at least two ways.
“Bacteria might contribute directly to plaque formation through the amyloid they produce,” says Chapman, “or they might contribute indirectly by triggering the precipitation of amyloid precursor proteins already present in the body.” Hultgren and his research team also are working to crystallize the combined A and B proteins to visualize how the two molecules interact.
“Learning that bacteria produce amyloid is a revelation,” says Paul Berg, Cahill Professor of Cancer Research and Biochemistry, Emeritus, at Stanford University School of Medicine and winner of the 1980 Nobel Prize in Chemistry.
“That discovery provides an additional vantage point from which to assess the role of amyloid production and accumulation in Alzheimer's disease and related neuro-pathologies. Hopefully, this model will reveal clues for preventing the devastating formation of amyloid plaques characteristic of those diseases."
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