CELL-DEATH OF ADULT PYRAMIDAL CA1 NEURONS AFTER INTRAVENTRICULAR-INJECTION OF A NOVEL PEPTIDE DERIVED FROM TRKA

Members of the nerve growth factor (NGF) family of neurotrophins bind to the second leucine-rich motif (LRM2) within the extracellular domai ns of their respective receptors (trkA, trkB, trkC). Small LRM2 peptid es have been recently demonstrated to selectively bind the neurotrophi ns revealing similar complex binding characteristics as full-length re ceptors, We extend our recent findings, showing that the peptides (A a nd C) do not block nerve fiber outgrowth through high affinity trk rec eptors in a ganglia bioassay, Since the highest concentration of neuro trophins [NGF brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3)lj is found in the hippocampus, the peptides were injected into the 3rd ventricle of anesthetized adult rats, The (NGF binding) LRM2- A peptide, but not the (BDNF binding) LRM2-B or the (NT-3 binding) LRM 2-C peptides, caused severe apoptotic neurodegeneration of hippocampal pyramidal CA1 neurons as revealed by; cresyl violet staining and the TUNEL reaction, The degeneration was protected by intrahippocampal inj ection of NGF-beta and by the non-N-methyl-D-aspartate (NMDA) antagoni st CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), indicating a glutamate rgic mechanism, In situ hybridization revealed that pyramidal CA1 neur ons did not express trkA and p75 receptor mRNA in sham and LRM2-A-lesi oned animals, If is concluded that the LRM2-A peptide represents a nov el peptide with properties to induce apoptotic cell death of pyramidal CA1 neurons and may be useful as an experimental agent. (C) 1997 Wile y-Liss, Inc.