Gene Slows Export of Toxic Protein

Photo: Bright yellow ring and black background

A ring of amyloid is visible in the
wall of an arteriole in the brain of
a patient who had Alzheimer's
disease; © URMC

The research provides new clues into the workings of a protein known as apolipoprotein E4, or ApoE4. People who carry two copies of the gene have roughly eight to ten times the risk of getting Alzheimer’s than others, according to previous research.

The new study asks how exactly ApoE4 increases a person’s risk for the disease. The findings point to differences in the way that amyloid-beta is removed from the brain depending on which ApoE protein is involved. Scientists found that when ApoE4 is present, the brain is less efficient at ridding itself of the toxic material.

“It is becoming more and more apparent that the brain’s ability to clear out amyloid-beta, through the vascular system and across the blood-brain barrier, is central to the development of Alzheimer’s disease,” said lead researcher Berislav Zlokovic. Once amyloid-beta gets out of the brain and into the body, it can be eliminated easily. “It is as if you have a pile of trash building up in the brain that you need to move away,” said Rashid Deane, one of the authors.

The research team found that a molecule known as very low-density lipoprotein receptor, or VLDLR, is an active – but slow – player in the removal of amyloid-beta from the brain. “We have known that the brain uses a molecule called LRP1, which is extremely efficient and acts like a fast ferry to remove amyloid-beta. Now we have found that there is another molecule involved, which works much more slowly, and it is especially active when amyloid is coupled to ApoE4,” Deane added.

The team showed that speedy LRP1 is central to removing amyloid-beta when ApoE2 or ApoE3 is involved, with the slower VLDLR picking up some of the slack. But when the form of the gene that puts people at risk, ApoE4, is involved, VLDLR nearly alone is responsible for hauling the amyloid-beta away.

The team found that LRP1 is able to export amyloid from the brain about 20 times faster than VLDLR. Consequently, in mice with the more efficient versions of the ApoE protein, ApoE2 and ApoE3, amyloid is cleared out of the brain at a rate about twice or three times as fast as in mice with the ApoE4 protein. Amyloid deposits accumulate in the brains of mice with the ApoE4 protein about ten to 15 times as much as in the brains of mice with either ApoE2.; Source: University of Rochester Medical Center