About one in nine people over the age of 65 has Alzheimer’s disease – and that number is growing rapidly.
With no existing cure, researchers are racing to find ways to prevent and treat the disease, which kills more than breast cancer and prostate cancer combined.
Thanks to a wave of progress in this area, scientists have discovered two new ways to manage Alzheimer’s disease in the future.
The first involves harnessing a powerful genetic mutation that reduces the harmful buildup of a protein in the brain. The second opens the door for a healthy layer of protective fat to return to the nerve fibers, thus keeping functional signaling between cells.
The two studies could be the first steps in the future development of therapies for Alzheimer’s disease.
Block the accumulation of toxic substances
One of the best ways to research Alzheimer’s disease is to look at people with a common genetic variant called APOE4 – one in four people carry it. And although these carriers have at least twice (and up to 12 times) the risk of developing Alzheimer’s disease, this is not the case for everyone.
The difference between those who do and do not contract this irreversible disease is the key to future prevention and treatment.
Researchers in Colombia found that some people with the APOE4 variant also have another mutation in their FN1 gene, a gene that provides instructions for making fibronectin.
Fibronectin is essential for the body to build tissue, which is why everyone has a copy of this gene. But this vital protein becomes a problem when it builds up around blood vessels, hindering normal signaling.
This can lead to a dysfunction of the blood-brain barrier, allowing harmful substances to enter the brain and making it more difficult to eliminate waste. This is often observed in APOE4 carriers with Alzheimer’s disease.
But the rare FN1 mutation identified by the Columbia researchers seemed to do the opposite: keep fibronectin in check. In one experiment, they found that zebrafish with this mutation had much lower accumulation of fibronectin than fish without the mutation.
This finding suggests several possible treatments, including preventing the accumulation of additional fibronectin. “This new study moves us from a genetic clue to a disease mechanism,” said author Caghan Kizil. “And with (the mechanism), ideas to reproduce this natural protection.”
Protect and reverse protective fat loss
MIT researchers have discovered a new pathway called Wnt that is disrupted in people with APOE4.
They found that people with APOE4 suppressed Wnt signaling, leading to a buildup of fat inside oligodendrocytes, which make myelin, the protective fatty insulation around nerve fibers.
Sufficient protection of the myelin around nerve fibers is essential for good communication between cells. Without it, lipids can build up in the brain without ever reaching where they are needed.
With defective oligodendrocytes, less myelin is produced. It is one of the first signs of Alzheimer’s disease before other symptoms appear.
What’s even more remarkable is that MIT researchers have found a way to correct this problem.
They found that they could inhibit an enzyme called GSK3b, thereby reducing fat buildup in these critical oligodendrocytes, making them function better and produce more myelin, thereby better protecting nerve fibers.
The authors believe that in the future, drugs could be developed to restore the Wnt pathway to produce more myelin. The key is an experimental compound called CHIR99021, which inhibits GSK3B.
This research “not only provides new insights into the cellular pathways contributing to lipid metabolism defects, but also has the potential to provide new targets for drug development,” said author Li-Huei Tsai.
Gn Health
