"We can monitor the process directly, and that gives us a different perspective," said Roberto Galletto, a postdoctoral scholar at UC Davis and first author on a paper published Sept. 20 on the Web site of the journal Nature.

In E. coli bacteria, molecules of an enzyme called RecA attach themselves along a DNA strand, stretching it out and forming a filament. A piece of complementary DNA lines up along side it, and pieces of DNA can be swapped in to repair gaps in the original strand. A similar protein, called Rad51, does the same job in humans.

"How RecA and Rad51 assemble into filaments determines the outcome of DNA repair, but very little is known about how assembly is controlled," said senior author Stephen Kowalczykowski, professor in the sections of Microbiology and of Molecular and Cellular Biology and director of the Center for Genetics and Development at UC Davis. Genes that control the human gene, Rad51, have been linked to increased risk of breast cancer.

Galletto attached a short piece of DNA to a tiny latex bead and placed it in a flow chamber, held by laser beam "tweezers." Fluid flowing past made the DNA stream out like a banner. Then he nudged it into an adjacent channel containing fluorescently-tagged RecA. After short intervals of time, he moved it back to the first chamber to observe the results.

By repeatedly dipping the same piece of DNA into the fluorescent channel, the researchers could see the RecA form clusters of four to five molecules on the DNA. Once those clusters had formed, the DNA/RecA filament rapidly grew in both directions. The measurements made in those experiments will be the baseline for future studies of both RecA and Rad51, Kowalczykowski said.

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Researchers were not able to stop the deterioration of insulin and its receptors. However, by administering PPAR, they were able to bypass the defects in insulin signaling and preserve the cells that need insulin to thrive. PPAR molecules go directly to the nucleus of cells and tell DNA to turn on or off genes that are normally regulated by insulin, thus preventing them from dying and allowing them to communicate with each other. The major effects of the PPAR treatments were to increase brain size, preserve insulin and IGF-II receptor bearing neurons, and preserve learning and memory.

"The trigger for dementia is the loss of insulin and IGF producing cells. The cells that need those growth factors subsequently die. This study shows you can block the second phase, which is responsible for dementia. This is great news for patients since you treat early stages of disease," de la Monte says.

Another promising result for Alzheimer's patients is that these drugs could be given in the form of a pill, de la Monte says. In the study, the drugs were injected to control the amounts administered.

"One of the most exciting findings was that peripheral (intraperitoneal) injection of the PPAR agonists either partially or completely rescued the brains from neurodegeneration," the authors write.

Alzheimer's appears to be caused by parallel abnormalities - impaired insulin signaling and oxidative stress, which is regulated by the genes NOS and NOX. The PPAR agonists treatments target both problems. They preserve the cells regulated by insulin and IGF, and they decrease oxidative stress, resulting in fewer lesions in the brain.

"If the diagnosis is suspected or patients are in the early phases of AD, there's a good possibility they could get treatment that will help them. It's possible that in the moderate phase, treatment will also help, but more work needs to be done to show that," de la Monte says.

Treatment is not likely to work in the late stages of the disease, she says, because the cells have already died.

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