Roles of glucose metabolism in brain aging and neurodegenerative diseases （脳の老化と神経変性疾患におけるグルコース代謝の役割）

講演要旨

Aging is associated with progressive declines in the functional integrity of the brain and elevated risks of developing age-related neurodegenerative diseases such as Alzheimer’s disease (AD). The brain is high in energy-demand, and most of the ATP in neurons is supplied by glucose metabolism. Aging and pathological conditions induce changes in both glucose availability and energy production, including declines in glucose uptake, electron transport chain activity, and aerobic glycolysis in the brain. By contrast, dietary restriction (DR) has been reported to have an anti-aging effect. Since DR causes circulating glucose concentrations to fall, the pro-aging effects of reductions in brain glucose metabolism are apparently contradictory. Thus, the exact roles of lowered glucose metabolism in age-associated declines in brain functions and disease pathogenesis is not fully understood.

We found that increasing glucose uptake protects against physiological declines during aging and neurodegeneration under disease conditions. By using Drosophila as a model system, we found that neurons in the aged brain suffer from ATP deficits, and increased neuronal glucose uptake ameliorates age-dependent declines in ATP. Increasing neuronal glucose metabolism enhanced the anti-aging effects of DR, suggesting that increasing neuronal glucose metabolism optimizes the anti-aging effects of energetic challenges.

We recently found that increasing glucose uptake protects against neurodegeneration induced by human tau, indicating its protective roles against disease conditions. Our results suggest that this process involves glial functions, which will be also discussed.