Peptides Derived from the Solvent-Exposed Loops 3 and 4 of BDNF Bind TrkB and p75NTR Receptors and Stimulate Neurite Outgrowth and Survival

Brain-derived neurotrophic factor (BONE) is critically involved in modeling the developing nervous system and is an important regulator of a variety of crucial functions in the mature CNS. BONE exerts its action through interactions with two transmembrane receptors, either separately or in concert. BDNF has been implicated in several neurological disorders, and irregularities in BDNF function may have severe consequences. Administration of BDNF as a drug has thus far yielded few practicable results, and the potential side effects when using a multifunctional protein are substantial. In an effort to produce more specific compounds without side effects, small peptides mimicking protein function have been developed. The present study characterized two mimetic peptides, Betrofin 3 and Betrofin 4, derived from the BDNF sequence. Both Betrofins bound the cognate BDNF receptors, TrkB and p75(NTR), and induced neurite outgrowth and enhanced neuronal survival, probably by inducing signaling through tha Akt and MAPK pathways. Distinct, charged residues within the Betrofin sequences were identified as important for generating the neuritogenic response, which was also inhibited when BONE was added together with either Betrofin, indicating partial agonistic effects of the peptides. Thus, two peptides derived from BONE induced neurite outgrowth and enhanced neuronal survival, probably through binding to BONE receptors. (C) 2009 Wiley-Liss, Inc.