Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response


  • F. Klempin
  • V. Mosienko
  • S. Matthes
  • D.C. Villela
  • M. Todiras
  • J.M. Penninger
  • M. Bader
  • R.A.S. Santos
  • N. Alenina


  • Cellular and Molecular Life Sciences


  • Cell Mol Life Sci 75 (19): 3625-3634


  • Physical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1-7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1-7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism.