Researchers discover drug that could fight brain cell death in people with Alzheimer's disease

One of the characteristic features of Alzheimer's disease, a debilitating disease characterized by deficits in memory and general cognitive decline, is the accumulation in the brain of a protein called b -amyloid. These proteins form "plaques" and bind to unique proteins on the surface of brain cells, called receptors, causing widespread cell death.

UCLA researchers have discovered a drug that prevents β-amyloid plaques from attaching to brain cells, thus preventing prolonged cell death. The study was published in the journal Nature Chemistry.

Dr. Lin Jiang, badistant professor of neurology, in collaboration with David Eisenberg, professor of chemistry and biochemistry and biological chemistry at UCLA, has identified the binding site of amyloid b plaque to its receptor by determining the three-dimensional structure. Knowledge of this interaction is an essential first step in the search for a drug to prevent the interaction between toxic proteins and brain cells. Jiang and his team then used computer software to help them in the drug selection process.

"We were looking for a molecule that could block the receptor as a shield, preventing the B-amyloid from binding to the brain cells and killing them," Jiang said.

In order to find molecular candidates to block the b-amyloid / brain cell interaction, Jiang and his colleagues searched for a library containing over 32,000 molecules. This list contained drugs approved for use in humans, which are currently undergoing clinical trials or that exist in the natural state. This meant that many of the features of the drug candidates were already known and that they were safe for human use.

Among these molecules, one drug, ALI6, has shown promising results in experiments on cells.

Jiang and his team cultured mouse brain cells and exposed them to toxic amyloid-β proteins, then treated some cells with ALI6 and compared the levels of cell death between groups. Treatment with ALI6 almost completely prevented cell death caused by b-amyloid, suggesting that the drug could possibly be studied to treat Alzheimer's disease.

ALI6 is a promising candidate. Not only is it nontoxic, but it can also pbad from the bloodstream to the brain, essential feature of any drug intended to treat disorders of the central nervous system such as Alzheimer's disease. In addition, ALI6 offers a distinct advantage over other treatments.

"Currently, many drugs are aimed at preventing amyloid-β-proteins from accumulating and turning into plaques because it's the dangerous form of protein," Jiang said. "However, when a person is diagnosed with Alzheimer's disease, many b-amyloid plaques have already formed, so the time window of treatment is already closing."

Alzheimer's disease is the sixth leading cause of death in the United States, with about 5.5 million people currently living with the disease.

The results of this study will need to be confirmed by additional tests on animals before the start of human studies.

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More information:
Qin Cao et al. Inhibiting the cytotoxicity of β-amyloid protein by its interaction with the cell surface receptor LilrB2 by a structure-based design, Nature Chemistry (2018). DOI: 10.1038 / s41557-018-0147-z