Synergistic Trophic Actions on Rat Basal Forebrain Neurons Revealed by a Synthetic NGF/BDNF Chimaeric Molecule

Abstract

Basal forebrain cholinergic neurons, which degenerate in Alzheimer's disease, respond to multiple trophic factors, including the neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This dual responsiveness prompted us to investigate the effects of a synthetic chimaeric molecule, containing the active domains of both NGF and BDNF. The NGF/BDNF chimaeric factor exhibited synergistic actions, and was 100-fold more potent than wild-type BDNF in enhancing survival of cultured dissociated basal forebrain cholinergic neurons. This effect was apparently due to true BDNF/NGF synergy, since addition of the two wild-type trophins simultaneously reproduced the effect of the chimaera. Synergy was selective for neurons which respond to both factors; substantia nigra dopaminergic neurons, which respond to BDNF but not NGF, exhibited no potentiation. The chimaeric factor thus revealed a synergy that may normally occur in the brain, and constitutes a potentially novel therapeutic agent with greater potency than naturally occurring individual trophins.

Site‐specific interactions of neurotrophin‐3 and fibroblast growth factor (FGF2) in the embryonic development of the mouse cochlear nucleus

“…For some factors, simultaneous exposure in combinations can produce effects not seen with each alone (Friedman et al, 1995;Mou et al, 1997Mou et al, , 1998. Synergistic and/or antagonistic effects of neurotrophic factors have been reported for NT3 and BDNF or TGF-5 in cochlear ganglion cell development (Hegarty et al, 1997;Hossain et al, 1997Hossain et al, , 2002Mou et al, 1997Mou et al, , 1998Marzella et al, 1999), for NGF and NT3 during axonal guidance of dorsal root ganglion (Cao and Shoichet, 2003), for BDNF and CNTF on motor neuron survival (Lindsay, 1996), and for neurotrophins and dopamine on survival of cortical neurons (Zhou et al, 1996a).…”

Time-dependence and cell-type specificity of synergistic neurotrophin actions on spiral ganglion neurons

“…Each neurotrophin exerts its own unique effects on target neurons (Valenzuela et al, 1993;Snider, 1994;Ghosh and Greenberg, 1995;Memberg and Hall, 1995;Thoenen et al, 1995), many of which are time-dependent in nature (Bruchman and Davies, 1993;Gaese et al, 1994;Airaksinen et al, 1996;ElShamy and Ernfors, 1996;Fariñ as et al, 1996). However, as has been shown with other growth factors (Heidemann et al, 1985;Chalazonitis et al, 1992;Mulderry, 1993;Wong et al, 1993;Morrison et al, 1994;Stoop and Poo, 1996), simultaneous exposure to combination of neurotrophins can produce effects not seen with each on its own (Friedman et al, 1995;Mou et al, 1997).Examination of these combinatorial actions of neurotrophins requires a model system with a relatively simple organization. The spiral ganglion possesses this characteristic because of the compartmentalization of two different receptor cell classes in the organ of Corti.…”

Subject Index To Volume 2

“…Like other secreted proteins, neurotrophins arise from proneurotrophin precursors (30)(31)(32)(33)(34)(35), that are proteoly-tically cleaved to produce mature proteins (12-13 kDa) [11]. The traditional view that these precursors were functionally inactive was recently rectified when they were shown to promote cell death by interacting with the p75 neurotrophin receptor.…”

“…involved in inflammation and immune responses, such as interleukin-1α (IL1α ), interleukin-4 (IL-4), interleukin-5 (IL-5), tumor necrosis factor-alpha (TNF-α), TGF-β and interferon-beta (IFN-γ) [27][28][29][30][31]. It is thought that NGF might act as an autocrine survival factor for memory B lymphocytes [32], stimulating immunoglobulin production and influencing B-and T-lymphocyte proliferation [33].…”