Nature: Preclinical study hints at how ApoE4 affects Alzheimer's risk
“Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," said principal investigator Berislav Zlokovic, MD, PhD, director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, in a statement. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system," he said, referring to the system of blood vessels that supply the brain.
The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties:
- ApoE2 is thought to play a protective role against both Alzheimer's and heart disease;
- ApoE3 is believed to be neutral; and
- ApoE4 confers a higher risk for both conditions.
Zlokovic and colleagues studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE. The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice's brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function and a loss of connections between brain cells.
"The study demonstrates that damage to the brain's vascular system may play a key role in Alzheimer's disease, and highlights growing recognition of potential links between stroke and Alzheimer's-type dementia," said Roderick Corriveau, PhD, a program director at NIH's National Institute of Neurological Disorders and Stroke, which helped fund the research. "It also suggests that we might be able to decrease the risk of Alzheimer's disease among ApoE4 carriers by improving their vascular health."
The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4. The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain. An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.
"These findings point to cyclophilin A as a potential new drug target for Alzheimer's disease," said Suzana Petanceska, PhD, a program director at NIH's National Institute on Aging, which also funded Zlokovic's study. "Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer's in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer's."
Zlokovic's study and others point to a complex interplay between beta-amyloid and ApoE4, according to the NIH statement. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain. On the other hand, Zlokovic's data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorized that this damage makes it harder to clear beta-amyloid from the brain. Some therapies under investigation for Alzheimer's focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.