Development of neuropeptides that promote neurogenesis in models of Alzheimer's and Parkinson's disease

Background: Recent studies suggest that alterations in adult neurogenesis in the olfactory region and hippocampus contributes to neurodegenerative pathology in models of Alzheimer's (AD) and Parkinson's disease (PD). We have previously shown that Cerebrolysin - a peptide mixture with neuroprotective activity promotes neurogenesis in amyloid precursor protein (APP) transgenic (tg) model of AD. Further analysis of Cerebrolysin components suggests that peptides with CNTF-like activity might be responsible for promoting neurogenesis. Identification of such smaller single peptide might be of value developing therapies for neurodegenerative disorders such as AD and PD. Methods: In this context, we have generated several CNTF peptides. One of these, an 11-mer peptide, Peptide 6, enhances the dentate gyrus neurogenesis, increases the level of MAP2 and synaptophysin, and improves spatial learning in normal adult C57BL6 mice. The objective of this study was to investigate Peptide 6 and one of its tetrameric fragments, Peptide 6A, in a novel tg model expressing red fluorescent protein (RFP) under the doublecortin (DCX) promoter (a reporter model for neurogenesis) and in APP tg mice. For this purpose, DCX-RFP tg mice and APP tg mice were treated with peptide 6, 6A, Cerebrolysin or saline control. Peptide 6 is 1162.64 Daltons and peptide 6A is 345.15. The dose was 5 nMol/animal/day IP injection for 4 weeks. Results: Confocal analysis of DCX cell density and morphology in the hippocampus and double immunolabeling with neuronal markers indicates that peptide 6 promotes neurogenesis to levels above Cerebrolysin, while peptide 6 increased neurogenesis above saline controls. Similarly, peptide 6A displays the ability to increase DCX immunoreactive neuroblasts in the brains of APP tg mice. Conclusions: Further analysis is underway with multiple markers of survival, proliferation and differentiation to characterize the activity of peptide 6A compared to Cerebrolysin. Identification of such smaller single peptide might be of value developing novel therapies for neurodegenerative disorders such as AD and PD.