Do Botched Proteins Add Up to Alzheimer's?

Scientists have a provocative new explanation for what may cause Alzheimer's disease in the majority of patients: a mistake in how certain proteins are made. The findings, reported in tomorrow's issue of Science, suggest that a faulty protein assembly line could help cause the plaques and tangles in the brain that are telltale signs of the degenerative disease.

Fred van Leeuwen and his colleagues at the Netherlands Institute for Brain Research in Amsterdam found evidence for faulty versions of two proteins implicated in Alzheimer's: b amyloid precursor protein (bAPP) and ubiquitin. While faulty proteins are usually blamed on mutated genes, the researchers could find nothing wrong with the genes for bAPP or ubiquitin. Instead, they turned up hints of a mistake in gene expression.

Cells require a molecule called mRNA to make a protein, and van Leeuwen found that in translating the gene's DNA into RNA, some cells had misread a sequence of nucleic acids--"GAGAG"--as "GAG." This resulted in a frameshift mutation that garbled the rest of the protein. Because the mistake shows up in cells of elderly people, the researchers wondered if it might play a role in Alzheimer's disease.

They applied antibodies--designed to tag garbled versions of ubiquitin and bAPP--to brain samples from Alzheimer's patients and people with Down syndrome, who develop early symptoms of Alzheimer's. The antibodies reacted with their target proteins in almost all the Alzheimer's and Down samples, but did not react with brain samples from young controls. In addition, analyses of mRNAs turned up examples of GA deletions in all the Alzheimer's and Down patients studied. The scientists speculate that as cells age, the protein assembly line becomes more error prone; as mutated proteins build up, they may somehow damage cells.

Reactions to the findings are mixed. Some researchers caution that the results are based on tests that could be misleading. John Hardy of the Mayo Clinic in Jacksonville, Florida, says the brain cells affected by Alzheimer's are so damaged that the antibodies could be staining many things besides the mutant bAPP and ubiquitin. And even if the mutant proteins are present, he says, "they are much more likely to be an effect than a cause" of AD brain damage.

But others, including Zaven Khachaturian, who is a scientific adviser for the Alzheimer's Association, say the work could help explain why age is the greatest risk factor for developing Alzheimer's, as the protein errors would presumably accumulate over time. Because similar mistakes could cripple thousands of proteins, they might contribute to other age-associated diseases and perhaps even aging in general.

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