Exciting new research, funded by the National Institutes of Health (NIH), has identified a variant ApoE4 gene that triggers a cascade of events that damages the brain's vascular system (blood supply ). Dr. Zlokovic and his team at the University of Rochester, the University of Southern California, used several different lines of mice that have been genetically engineered to produce their findings.
The ApoE gene has been linked to the risk of developing late onset Alzheimer’s disease but it was unclear how that happened. It is known that people who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not.
The ApoE gene encodes a protein that regulates levels of cholesterol and other lipids (fats and oils, waxes, phospholipids, steroids like cholesterol) in the body. There are 3 types of the gene. ApoE2 is believed to play a role in protecting us against Alzheimer’s disease and heart disease, ApoE3 is thought to be neutral, ApoE4 means we have a higher risk for both Alzheimer’s and heart disease.
This research found that mice who only made ApoE4, or made no ApoE at all, had a leaky blood-brain barrier that allowed harmful proteins into their brains. Over a few weeks this caused loss of small blood vessels and loss of connections between brain cells and changes in brain function. The blood-brain barrier is very important as it protects the brain from foreign substances in the blood that may injure it. It also protects the brain from hormones and neurotransmitters in the rest of the body and maintains a constant environment for the brain.
The research also found that ApoE2 and ApoE3 helps to control levels of an inflammatory molecule called cyclophilin A, but ApoE4 does not. Cyclophilin is known to be important in diseases of the cardiovascular system.
Alzheimer's disease research has, for many years, been focused on amyloid beta, a protein structure that accumulates in the brains of patients with Alzheimer's disease. This study, published in the prestigious journal Nature, shows that there are other causes of the disease that will be important in the development of drugs to prevent, reverse or arrest further damage of Alzheimer’s.
Clearly more research will be needed to increase our understanding of vascular risk factors contribution to Alzheimer’s disease.
Bell RD et al. "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A." Nature, published online May 16, 2012.