Neurotrophins in development and disease of the nervous system

Nerve growth factor (NGF) was the first member of the neurotrophin family to have been identified -over 50 years ago- and it is only comparatively recently that our laboratory realised that the nerve growth factor TrkA kills neurons in the absence of its ligand. This finding explains the long known depend on NGF of TrkA-expressing neurons (for review, see Ref. 1). BDNF, the second member of the family now receives considerable attention as it is widely distributed in the brain and a key effector of neuronal plasticity, a notion supported by the analysis of BDNF polymorphisms in humans. As decreased BDNF levels are widely appreciated to correlate with compromised brain function, efforts are now underway to increase BDNF signalling using indirect strategies. We found that Fingolimod, a sphingosine analogue widely used for the treatment of multiple sclerosis, increases BDNF levels in the brain. In animal models of Rett syndrome, a frequent from of mental retardation in young girls, we found that Fingolimod injections restore close to normal levels of BDNF and markedly improve the locomotor phenotype of these animals. These results formed the basis of a clinical trial initiated at the University Hospital in Basel aiming at testing the possible benefits of Fingolimod administration to children suffering from Rett syndrome. As BDNF is not only present in the brain, but also in the blood of humans and primates, we have begun to explore its possible role and potential meaning as a biomarker. As a first step, we recently identified megakaryocytes as the cellular source of BDNF in human blood and found that surprisingly, these cells express the BDNF gene using the same promoters as neurons2. These findings provide a possible explanation why BDNF levels in blood may reflect BDNF levels in the brain, a tentative a posteriori justification for the extensive use of BDNF as a biomarker in human blood by neurologists and psychiatrists. Whether or not blood-derived BDNF exerts a functional role in the brain and other organs is also being explored using a new mouse model mimicking the situation in humans.