Researchers tap into nature's way of clearing waste to treat Alzheimer's disease

Researchers at the Washington University School of Medicine in St. Louis (WUSTL) have found a new pathway that could be exploited to clear the brain of its toxic waste and help prevent neurological diseases, a university press release said.

The accumulation of the amyloid beta protein in the brain has been a well-established cause of Alzheimer's disease. Research has been ongoing on ways to prevent the accumulation of the protein in the first place to prevent the disease or remove it using certain drugs that can cross the blood-brain barrier. However, this strategy has had very little success so far.

Learning from the basics

Researchers at WUSTL were studying the basic process of how proteins are made inside the cell when they noticed that proteins do not follow these processes to the letter.

Typically, the cellular machinery encodes a start sign and an end sign for the protein to be made. However, sometimes, protein-making machinery does not stop at the end sign and continues to make a longer tail for the protein. In technical terms, this phenomenon is called a readthrough.

WUSTL researchers studied a brain protein called aquaporin 4 when they noticed this readthrough on some proteins. At first, they dismissed it as poor quality control on the part of the cellular machinery. However, when they compared the gene sequences for the protein across species, they found that it was conserved, the scientific term for broadly similar. Even more striking, it was only found in structures that were important for waste clearance.

Working with astrocytes

The researchers then created more tools to study if the longer and shorter forms of aquaporin 4 behaved any differently in the brain and found that they did. The longer form of aquaporin-4 was closely associated with astrocytes - support cells that help maintain the blood-brain barrier.

Astrocytes also have specialized structures that scientists call endfeet, which wrap around the brain's blood vessels. This helps them regulate the blood flow and flush out wastes from the brain.

Presuming that the long form of the aquaporin-4 protein increases waste clearance, the researchers screened over 2,560 compounds to determine, which of them might increase aquaporin's readthrough. However, they found only two. One was sulphaquinoxaline, an antibiotic commonly used in the meat and poultry industry while the other was apigenin, a component found in chamomile, parsley, onions, and other plants.

The researchers then tested these two compounds for their ability to clear beta amyloids from the brains of mice genetically modified to have high protein levels. Both these substances could remove beta-amyloid from mice brains faster than control liquids that the researchers used in their experiments.

The researchers think that the same strategy could be applied to clear alpha-synuclein, the protein attributed to the development of Parkinson's disease. While sulphaquinoxaline is not meant for human consumption, the researchers have also warned against trying to consume apigenin either in supplement form or through edible plants to keep Alzheimer's away.

This is the beginning of the research, and more work must be done before it is used as a treatment or prevention. The findings of the study were published in the journal Brain.

Abstract

Alzheimer’s disease is initiated by the toxic aggregation of amyloid-β. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer’s disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer’s disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance.

Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-β clearance in vivo, which depends on AQP4X.

This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease.