Sci. Aging Knowl. Environ., 12 November 2003
Vol. 2003, Issue 45, p. nw153
[DOI: 10.1126/sageke.2003.45.nw153]


Brain Lubricant

Antiatherosclerosis protein helps brain cells shuttle cholesterol carrier

R. John Davenport

Key Words: ApoE4 • ATP-binding cassette

NEW ORLEANS, LOUISIANA--When the body loses control of cholesterol, the heart isn't the only victim; the brain also suffers (see "Greasing Aging's Downward Slide"). In preliminary work presented here on 6 November at the Neurobiology of Aging meeting, researchers revealed new details of how a protein that fights fat buildup in blood vessels helps keep the brain healthy.

In many tissues, this protein--called ABCA1--ferries cholesterol from inside cells to lipoproteins outside. This ability is crucial for helping prevent cholesterol buildup in cells such as macrophages, which chew up damaged cells and recycle or dispose of cholesterol. Mutations in the gene for ABCA1 result in Tangier disease, a rare condition in which patients accumulate cholesterol in blood vessels, liver, spleen, and other tissues, leading to atherosclerosis and impaired organ function. And mice without ABCA1 develop atherosclerosis, whereas those with extra ABCA1 resist it. Neuroscientist Cheryl Wellington of the University of British Columbia in Vancouver, Canada, had previously found that brain cells make ABCA1, but she wasn't sure whether the protein plays the same role in the brain as it does elsewhere in the body. She also wondered whether brain ABCA1 helps deliver cholesterol from cells to a lipoprotein called apolipoprotein E (ApoE). If so, ABCA1 might link cholesterol with neurodegeneration, because people who carry a certain version of the ApoE gene stand a higher-than-normal chance of developing Alzheimer's disease (see "Detangling Alzheimer's Disease").

To investigate this question, Wellington, Veronica Hirsh, and their colleagues obtained microglia--the brain's equivalent of macrophages--from mice that lack the gene for ABCA1 and tested whether the dearth of the protein hindered these cells from handing off cholesterol to ApoE. They filled microglia with radioactive cholesterol, added various human lipoproteins to the cells' surroundings, and assessed whether the lipoproteins grabbed the tagged cholesterol. All ApoE versions picked up the same amount of cholesterol, regardless of whether the cells that exported it carried ABCA1.

The researchers next wondered whether ABCA1's putative connection with ApoE lies in an ability to transport the lipoprotein itself. Previous studies had suggested that ABCA1 encourages macrophages in blood to release ApoE, so the team tested whether it performs a similar task in microglia. In culture, microglia made normal amounts of mouse ApoE (of which there's only one type) but dispersed 60% less ApoE into the surroundings than normal. Together, the results suggest that ABCA1 doesn't influence cholesterol-loading onto ApoE molecules in the brain, but that it plays an important role in "getting ApoE out of the cell," says Wellington. Whether ABCA1 directly or indirectly spurs ApoE export isn't yet clear, nor is whether the different human ApoE forms are exported to varying extents in the absence of ABCA1. Wellington notes that mice without ABCA1 carry 50% less ApoE in their brains than normal mice do; she isn't sure why, but perhaps cells in intact brains trash ApoE quickly if they can't dispense it.

ABCA1 "is going to be critical for the ApoE story [in Alzheimer's disease]," predicts neuroscientist Carol Colton of Duke University in Durham, North Carolina. The results could answer some questions about ApoE. For instance, when brain cells are stirring up inflammation, they withhold ApoE; when inflammation subsides and repair begins, cells release ApoE. But scientists don't know what activates ApoE export. "ABCA1 could be that switch," says Colton. Wellington wants to test whether the absence of ABCA1 exacerbates neurodegeneration in mice that carry human ApoE. Such results could help researchers clarify how twists in cholesterol metabolism blunt brain power.

--R. John Davenport

November 12, 2003
  1. V. Hirsh et al., ABCA1 modulates ApoE in brain and plasma. 4th Neurobiology of Aging Conference, 6-7 November 2003, New Orleans, Louisiana. [Meeting Web Site]
Citation: R. J. Davenport, Brain Lubricant. Sci. Aging Knowl. Environ. 2003 (45), nw153 (2003).

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