Sci. Aging Knowl. Environ., 10 September 2003
Apoplectic From ApoE
Protein abets amyloid buildup in brain's blood vessels
Key Words: microhemorrhage parenchymal plaque
Apolipoprotein E (apoE) helps perpetrate Alzheimer's disease, and different varieties of the molecule shift the odds of developing dementia. New research adds a charge to the protein's rap sheet, indicating that it accelerates blood vessel deterioration that can result in a fatal stroke. The findings suggest that hampering apoE might forestall the sometimes deadly accumulation.
ApoE encourages the protein amyloid to congeal into globs that can wound neighboring brain cells. But amyloid also infiltrates the walls of blood vessels in the brain, a condition known as cerebral amyloid angiopathy (CAA) that strikes about 90% of Alzheimer's sufferers. A -amyloid-infested capillary or arteriole can leak or shut, causing strokes that can undermine cognitive abilities or even kill. Researchers don't know what spurs the buildup, but some evidence implicates apoE. Patients with a version of apoE that is particularly good at spurring -amyloid aggregation are more susceptible to CAA. And neurologist David Holtzman of Washington University in St. Louis, Missouri, and colleagues showed that banishing apoE slows -amyloid accumulation in blood vessels, at least in one mouse model of Alzheimer's disease.
To probe the question further, Holtzman and colleagues studied two lines of mice engineered to pump out extra amyloid, one known as PDAPP, the other as APPsw. Both lines showed -amyloid pileup in blood vessels and tiny brain hemorrhages characteristic of CAA. The researchers then bred each line with mice lacking the gene for apoE, thus producing two new lines that can't make the protein. Eliminating apoE squelched CAA symptoms. Both groups of apoE-lacking rodents showed no -amyloid buildup in blood vessels. In the PDAPP line, removing apoE slashed the number of strokes by more than 66%, and almost none erupted in the APPsw animals. Because mice lacking apoE still amass -amyloid plaques elsewhere in the brain, the results suggest that "apoE has an even more profound impact on amyloid deposition in blood vessels than in the brain," says Holtzman. How apoE triggers CAA is unclear, but Holtzman thinks it might hamper the normal removal of amyloid from the brain, allowing it to get jammed in the vessel walls.
"The results are very persuasive that you need apoE to get deposits [in the blood vessels] and to get bleeding," says neurologist Steven Greenberg of Harvard Medical School in Boston. The work also backs the notion that blocking apoE might thwart CAA, which today is untreatable, he says. Different versions of apoE have different effects on CAA, says neuropathologist Harry Vinters of the University of California, Los Angeles, and researchers need to figure out why. For example, people who carry one form of the protein are more likely to show vessel buildup--and more likely to develop Alzheimer's disease--but people with a different version are more susceptible to brain bleeding. Understanding the difference might provide clues about how to prevent apoE from conspiring with amyloid to damage the brain's blood vessels.
--Mitch Leslie; suggested by Galynn Zitnik
September 10, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150