Sci. Aging Knowl. Environ., 28 January 2004
Mice without ApoE and related protein unexpectedly accumulate -amyloid deposits
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/4/nf12
A person can toss her wadded-up burger wrapper into either the gutter or a trash bin. New work establishes that ApoE, a protein connected to Alzheimer's disease (AD), makes a similar choice. Mouse studies have suggested that ApoE encourages formation of the -amyloid plaques that gum up patients' brains. But scientists now suggest that ApoE helps clear amyloid from the brain before it forms plaques. The results warn that targeting ApoE as an AD treatment will require balancing its positive and negative influences.
Having a particular flavor of the ApoE gene increases the risk of AD, but how the gene contributes to the disease is mysterious. Mice have only one version of the gene, but scientists are using them to probe connections between ApoE and AD. Mice engineered to accumulate -amyloid clumps develop fewer plaques if they lack ApoE. A related protein called clusterin appears to behave similarly: Plaque-prone mice that don't make the molecule maintain relatively clean brains. Neuroscientist David Holtzman and colleagues at Washington University in St. Louis, Missouri, wondered whether animals missing both proteins would fare even better.
The researchers generated mice with a plaque-promoting mutation that also lack ApoE and clusterin. To their surprise, the animals accumulated an unusually large number of -amyloid molecules in the space between neurons and carried more plaques at 12 months than did animals missing only one of the proteins. ApoE and clusterin don't boost production of -amyloid protein, so the team tested whether they control its disposal. The researchers blocked the enzyme that creates amyloid in 3-month-old mice and collected samples of the fluid between brain cells. -amyloid molecules disappeared faster in animals carrying ApoE than in rodents missing either both proteins or just ApoE. Holtzman isn't sure how rodents without ApoE avoid accumulating clumps despite the slow decline in amyloid, but he notes that the animals make two forms of amyloid; the proportion of these forms in ApoE-lacking mice hinders clumping, previous studies suggested. The results imply that ApoE helps dispose of soluble amyloid before it clumps. Researchers know that ApoE binds to amyloid; in the cell, ApoE might escort it out of the brain or to disposal machinery, but the protein might also concentrate it in particular brain regions, thereby encouraging aggregation. The balance between those two outcomes might determine whether ApoE spurs or inhibits plaque formation.
The study "should help change people's view of how ApoE is influencing amyloid," says physiologist Gregory Cole of the University of California, Los Angeles. Next, researchers should plug human ApoE into mice and test whether it also fosters -amyloid removal, says molecular neuroscientist Robert Vassar of Northwestern University School of Medicine in Chicago. If it does, researchers should be cautious about targeting ApoE as a treatment for AD. Blocking its plaque-spurring capacity might also thwart its ability to dispose of amyloid and keep the neighborhood clean.
January 28, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150