Sci. Aging Knowl. Environ., 20 February 2002
Vol. 2002, Issue 7, p. nw22
[DOI: 10.1126/sageke.2002.7.nw22]


Getting a Grip by Losing One: A protein slip could trip up Alzheimer's (Alzheimer's disease)

Dan Ferber;2002/7/nw22

Key Words: Alzheimer's disease • APP • amyloid precursor protein • FE65 • genetics • polymorphism

Abstract: New work suggests a mechanism by which a rare form of a gene protects people from so-called very late onset Alzheimer's disease (AD). Proteins made from this gene clutch the amyloid precursor protein (APP), the source of the main ingredient in the senile plaques that characterize the disease (see "Detangling Alzheimer's Disease"). Now researchers have shown that the beneficial version of the protein has a relaxed hold on APP. Perhaps in brain cells, as elsewhere in life, it's sometimes best to let go.

In 1998, Hu and colleagues found an unusual form of a gene called FE65 that is about twice as common in healthy people 75 and older as in AD patients in the same age group. The rare variant apparently wards off a type of AD that starts very late in life, and the researchers wondered how. Subsequent work from other groups showed that the FE65 protein helps turn genes on and off and that it binds to APP, which is embedded in the cell membrane. The embrace with APP, however, keeps FE65 out of the nucleus, where genes reside.

The rare variant differs from the standard FE65 gene at two short spans near one end. Those stretches sit in an intron: a piece of RNA that's removed as the cell edits newly minted RNA. Although introns are chopped out, their sequences can influence how the remaining sequences are spliced together. The researchers guessed that RNA from the unusual FE65 is spliced differently from that encoded by the ordinary gene, leading to an altered protein.

Hu and colleagues found that the rare variant produces a truncated FE65 protein missing a long stretch at its tail end. That part of FE65 normally grasps APP, which inspired the team to compare how well the normal and shortened FE65 proteins bind to APP. The unusual form of FE65 grips much more weakly than the common version does. That finding and other recent work suggests three plausible mechanisms by which the rare variant can lower the risk of AD, Hu says--none of which are mutually exclusive. A loose hold on APP might free FE65 to enter the nucleus, where it might activate other genes that shield against AD. It could trigger the cell skeleton remodeling needed for the growth of new neural connections. And it could curtail the slicing and dicing of APP that yields a dangerous fragment believed to damage neurons, she suggests.

The new results about altered RNA splicing and protein binding "look convincing," says geneticist Alison Goate of Washington University in St. Louis, Missouri. But in the meantime, the original data linking the rare FE65 variant and resistance to AD have become less compelling, because only two of five subsequent studies reproduced the result, she says: "Although it's a very interesting finding, it needs to be widely replicated in a number of populations" before this gene could be used to predict whose mind might be seized by the disease. But if it does presage late-onset AD risk, keeping a distance between FE65 and APP might mean keeping a close grip on your mind.

--Dan Ferber

Q. Hu, B. H. Cool, B. Wang, M. G. Hearn, G. M. Martin, A candidate molecular mechanism for the association of an intronic polymorphism of FE65 with resistance to very late onset dementia of the Alzheimer type. Hum. Mol. Genet. 11, 465-475 (2002). [Abstract] [Full Text]

Citation: D. Ferber, Getting a Grip by Losing One: A protein slip could trip up Alzheimer's (Alzheimer's disease). Science's SAGE KE (20 February 2002),;2002/7/nw22

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