Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis

In multiple sclerosis (MS), brain-derived neurotrophic factor (BDNF) provides neuroprotection, but can also promote disease through the maintenance of autoreactive T cells. One aspect that has not been explored yet in MS is related to the opposite functions of BDNF protein isoforms consisting of the pro-BDNF precursor, which has pro-apoptotic effects, and two proteolytic isoforms, the mature BDNF with pro-survival effects and truncated BDNF, with unknown functions. Using ELISA and semi-quantitative Western-blot we determined the relative serum levels of BDNF isoforms in 20 relapsing-remitting MS patients without any disease modifying therapy and 20 age and gender-matched healthy controls and searched for clinical correlates. Total serum BDNF was lower in MS than in HC. We demonstrate that the capture and detection antibodies of the ELISA kit from Promega are able to recognize all three isoforms but with different efficiency. Using Western-blot analysis, we show that the percentage of serum mature BDNF and pro-BDNF with respect to total serum BDNF was significantly decreased, while truncated BDNF was increased. No correlation between BDNF isoform percentage and clinical or demographic features was found. Serum Fas (sFas) was increased. These results support and expand the current hypothesis on the role of BDNF in multiple sclerosis, in that low pro-BDNF and high sFas might result in a failure to limit autoreactive T cells by apoptotic deletion and decreased mature BDNF may not provide enough neuroprotection, while truncated BDNF percent increase could be a compensatory mechanism. Hence, future studies on MS should take into account BDNF proteolytic processing.