Bacteria Suggest New Approach To Alzheimer's Therapy
Science Daily — New insights into how bacteria form fibers called curli offer 
intriguing clues to the formation of harmful protein tangles in diseases such 
as Alzheimer's, Huntington's and Parkinson's, University of Michigan 
researchers report. 

The research builds on a chance discovery that U-M microbiologist Matthew 
Chapman and co-workers made five years ago. In research initially aimed at 
understanding urinary tract infections, they discovered that the common 
bacterium Escherichia coli makes and employs amyloid fibers, the same types 
of fibers that are the calling cards of many neurodegenerative diseases. 
Until then, amyloids were considered "biological blunders" that occurred only 
when proteins misfolded into deviant forms that aggregate into harmful 
clumps, Chapman said. But his work showed that bacteria produce amyloid 
fibers "by design" and use them to adhere to surfaces and to interact with 
other bacteria.
Since making the discovery, Chapman and his lab group have been exploring 
bacterial amyloids, using an approach that blends microscopy, biochemistry 
and genetics. In the current work, the researchers reveal details of how 
curli—functional amyloid fibers assembled by E. coli and certain other 
bacteria—are assembled.
In both bacteria and humans, amyloids form through a process known as 
nucleation, in which protein subunits link together in a coordinated fashion. 
Just as a snowflake begins as a speck of dust around which water freezes, an 
amyloid fiber also requires a template or nucleus to begin forming.
In bacteria, two proteins—CsgA and CsgB—are involved in the process, each with 
its own precise function. The job of CsgA is to build up amyloid fibers, but 
only after CsgB—dubbed "the nucleator"—has set the stage.
"What we've discovered is the molecular mechanism of bacterial amyloid 
nucleation," said graduate student Neal Hammer, who is lead author on the 
paper. "The B protein presents an amyloid-like template to the A protein, 
which builds on that template to form a fiber."
Having one protein in charge of nucleation and the other in charge of fiber 
elongation is a clever strategy that allows for control of a process that 
otherwise might occur unpredictably, as seems to happen with 
disease-associated amyloids.
"Control is achieved by keeping the A and B proteins apart until they get to 
the cell surface," said Chapman, an assistant professor in the Department of 
Molecular, Cellular and Developmental Biology. "At the cell surface, they 
come together, resulting in controlled amyloid formation."
Because CsgB speeds the amyloid fiber formation process, it prevents the 
buildup of potentially toxic intermediates, Chapman said. Similarly, studies 
of functional amyloids in other organisms have found that the fibers always 
form rapidly, bypassing intermediate steps. Such observations suggest new 
approaches to treating and preventing diseases such as Alzheimer's. 
"Conventional wisdom has been that if we can prevent fiber formation, we can 
prevent these diseases," Chapman said. "But if you think about what nature is 
telling us, it's the exact opposite. I think what these functional amyloids 
are telling us is that maybe fiber formation is a process that should be 
happening, and that problems arise when the process goes too slowly and 
favors these toxic intermediates. Maybe what we should be doing is forcing 
the protein to form fibers in ways that skip the toxic intermediate steps."
Sue Wickner, an investigator at the National Institutes of Health working in 
the field of protein folding, said, "The Chapman group has been carrying out 
exciting work that provides novel insight into how amyloid fibers are made. 
The research has important implications toward a better understanding of the 
devastating human diseases involving aberrant protein folding, such as 
Alzheimer's, Creutzfeld-Jacob and dialysis-related amyloidosis."
Results were published online in the Proceedings of the National Academy of 
Sciences during the week of July 9-13. In addition to Chapman and Hammer, 
Jens Schmidt, a visiting diploma student from Germany, is a co-author on the 
paper. The researchers received funding from the National Institutes of 
Health and the Michigan Alzheimer's Disease Research Center.
Note: This story has been adapted from a news release issued by University of 
Michigan.

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn