Aquaporin 4 for a healthier brain

Cleaning up the toxic waste that gets accumulated in internal organs is not easy

A simple bath may help you clean up your outer body. However, cleaning up the toxic waste that gets accumulated in your brain or other internal organs is not that easy. When a toxic protein like amyloid (produced in the bone marrow) gets accumulated in the brain or other organs, it may cause dysfunction of various systems.

Accumulation of beta amyloid in the brain is seen as the first indicator of the development of Alzheimer’s dementia. A 2018 research article published in Proceedings of the National Academy of Sciences of the United States of America had shown that acute sleep deprivation is an important reason that impacts the beta amyloid burden in brain regions. Millions have been poured into the research of finding ways to clear amyloid before the appearance of cognitive symptoms of Alzheimer’s. Immunotherapy targeting beta amyloid is in clinical trials, but they have shown limited success. Now, a group of researchers has found a novel way to increase the clearance of toxic waste by ramping up a tricky process known as readthrough.

When the brain synthesises a protein called Aquaporin 4, it sometimes creates an extra tail at its end. This is because the protein synthesising machinery did not stop at the stop sign. This process of crossing the stop sign during protein synthesis is called readthrough. The researchers thought this quirky mechanism was nothing more than an occasional failure in the protein manufacturing process. However, when they analysed the gene sequence, it had shown a striking pattern in the brain—it was in structures that are important for waste clearance.

The researchers then created tools to analyse whether the long-form Aquaporin 4 behaved differently compared with the regular form. They found the long form in the “end feet” of astrocytes—support cells that help in maintaining a barrier between the brain and the rest of the body. The “end feet” of astrocytes wrap around the blood vessels and regulate blood flow, which means it is the best place to be if a compound’s job is to flush toxic waste out into the bloodstream.

Assuming that increasing the amount of long-form Aquaporin 4 might increase the waste clearance, researchers then screened 2,560 compounds for the ability to increase readthrough. They found two compounds: apigenin, a compound found in onions and other edible plants; and sulphaquinoxaline, a veterinary antibiotic used in the poultry industries. Then, the researchers studied the effect of these compounds in genetically engineered mice with high levels of amyloid in their brains, and they found promising results. Their study was published in the journal Brain. Mice models have shown that reducing the amyloid levels by 20 to 25 per cent will stop its buildup in the brain.

The accidental finding about readthrough could open up a novel way to treat not just Alzheimer’s, but other neurodegenerative diseases that involve protein aggregation in the brain.