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PNAS: blocking hexokinase-2 improves cerebral clearance of neurodegenerative proteins

Scientists at Nanyang Technological University Singapore discovered a way to activate immune cells in the brain called microglia to eliminate toxic amyloid proteins that cause Alzheimer’s disease. This is reported in the article published in Proceedings of the National Academy of Sciences (PNAS).

The researchers’ conclusions are based on the study of a molecule called a translocator protein, responsible for transporting nutrient vesicles along the filaments of the cytoskeleton. Drugs that activate this protein have already been shown to reduce the deposition of toxic substances in the brain, which improves the condition of a mouse model of Alzheimer’s disease.

With inactivation of the translocator protein, mouse microglia had problems providing enough metabolic energy and could not remove beta-amyloid with sufficient efficiency, leading to poor animal health. At the same time, the enzyme hexokinase-2 is activated in the microglia, which metabolizes sugar to compensate for the lack of energy, but it was still not enough to eliminate beta-amyloid. In addition, hexokinase-2 is attached to the cell’s energy-generating organelles, the mitochondria.

Hexokinase-2 is also activated in microglia when exposed to particularly toxic forms of beta-amyloid, as occurs in Alzheimer’s disease. Scientists believe this discovery partly explains why microglia fail in patients with neurodegenerative diseases and as they age.

Researchers have developed a way to turn off the functions of hexokinase-2, allowing microglia to no longer depend on an inefficient way to generate energy. Experiments have shown that this only works if the enzyme stops “sticking” to the mitochondria, and simply inactivating the hexokinase does not help. This provides a basis for the development of future drugs against neurodegenerative diseases.

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