ApoE4 Helps Weaken Blood-Brain Barrier

A genetic variant of apolipoprotein E (ApoE) damages the blood vessels that feed the human brain, possibly contributing to the deleterious effects of Alzheimer’s disease, according to a study (Nature, DOI: 10.1038/nature11087). Scientists have known that ApoE4, one form of the protein that carries lipids through the circulatory system, is strongly associated with Alzheimer’s. But they haven’t understood why. Researchers led by Berislav V. Zlokovic, formerly at the University of Rochester and currently at the University of Southern California, have now determined that the presence of ApoE4 in the brain enables an inflammatory protein called cyclophilin A to run rampant, triggering a biochemical pathway that eventually leads to weakening of the blood-brain barrier. Other variants of ApoE—ApoE2 and ApoE3—keep cyclophilin A in check. Using multiphoton microscopy, Zlokovic’s team found that mice engineered to express human ApoE4 have leaky blood vessels in their brains and a higher level of cyclophilin A than their normal counterparts do. A weaker blood-brain barrier, the researchers say, can lead to the brain’s uptake of neurotoxic proteins from the blood. When treated with cyclosporin A, an immunosuppressant that binds cyclophilin A, ApoE4 mice displayed decreased blood vessel damage.

When administered to mice engineered to carry ApoE4 (left), cyclosporine A prevents blood vessels in the brain from leaking (right), as shown in these microscopy images. Nature